A rare X-linked syndromic intellectual disability characterized by global development delay, postnatal growth retardation leading to short stature, facial dysmorphism, short hands with tapering fingers and progressive skeletal abnormalities including kyphoscoliosis and pectus carinatum/excavatum. Intellectual disability ranges from mild to severe.

Summary:
Epidemiology
The exact prevalence is not known but is estimated to be 1/50,000 to 1/100,000. Male patients are generally moderately to severely affected while most female carriers have mild features.
Clinical description
Severe clinical presentation was reported in the first male patients described. Following the wide application of molecular genetic testing, the phenotype is now recognized as very variable. Affected newborn males often show hypotonia and hyperlaxity of joints with normal growth parameters. Growth retardation and global developmental delay become visible in the first years of life. The facial dysmorphism visible in late childhood and adulthood include prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthic folds, prominent ears, wide mouth, thick lips with everted lower vermilion, thick nasal alae, and septum. Oral findings include a high narrow palate, a midline lingual furrow, hypodontia, and peg-shaped incisors. Microcephaly is common. Hands are short, soft, and fleshy with skin/joint laxity and tapering fingers. Full and fleshy forearms can be present in childhood. Skeletal abnormalities appear gradually and may include spinal kyphoscoliosis (often progressive) and pectus carinatum/excavatum. Cognitive impairment is variable in severity. Other neurological findings may include epilepsy, progressive paraplegia and stimulus-induced drop attacks (SIDAs). Brain abnormalities have been reported but without a consistent pattern. A happy personality is common although behavioral abnormalities can be present. Other less frequent manifestations are sensorineural hearing loss and heart anomalies. Final stature is usually below the third percentile.
Etiology
Coffin-Lowry syndrome (CLS) is caused by pathogenic variations in the RPS6KA3 gene (Xp22.2-p22.1), which encodes ribosomal protein S6 kinase alpha-3, a growth-factor-regulated protein kinase.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by the following genetic tests: sequencing of RPS6KA3 or Intellectual Disability-related Next Generation Sequencing panel that includes this gene. If sequencing results are negative, multiplex ligation-dependent probe amplification analysis should be performed in order to assess deletions or duplications.
Differential diagnosis
Differential diagnosis includes Alpha-thalassemia-X-linked intellectual disability (ATRX) syndrome, Borjeson-Forssman-Lehmann syndrome, FG syndrome type 1, Williams syndrome and Pitt-Hopkins syndrome.
Antenatal diagnosis
Prenatal genetic counseling should be offered to parents of patients who are hemizygotes for the pathogenic variant to discuss genetic risk and reproductive options.
Genetic counseling
Coffin-Lowry syndrome is an X-linked dominant disorder. About two-thirds of cases occur de novo. The risk of recurrence for the sibs of a proband depend on the mother's genotype. If the mother is a carrier of the pathogenic variation, the risk of transmitting the variant in subsequent pregnancies is 50%. Male offspring inheriting the mutation are affected, and female carriers can be unaffected or show milder phenotypes (Symptomatic form of Coffin-Lowry syndrome in female carriers). If the mother is not a carrier, the risk of recurrence is very low and linked to the possibility of germinal mosaicism.
Management and treatment
Management requires an early multidisciplinary approach. Kyphoscoliosis/spinal stenosis and SIDAs should be recognized and treated to avoid secondary complications.
Prognosis
Prognosis is poor and depends on the severity of the disease. Life span is reported to be reduced.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Stefania BIGONI | ITHACA* - Pr Alessandra FERLINI | ITHACA*

                                * European Reference Network


A rare genetic syndromic intellectual disability of broad phenotypic range characterized by developmental delay and variable clinical features which most commonly, but not consistently, include aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, and coarse facial features.

Summary:
Epidemiology
More than 150 cases of genetically confirmed Coffin-Siris syndrome (CSS) have been clinically reported to date. Exact prevalence and incidence are not known but the disorder is probably under-recognized.
Clinical description
Coffin-Siris syndrome is a clinically and genetically heterogeneous disorder. It involves a wide range of major and minor clinical findings. Characteristic major features include mild to severe developmental or cognitive delay (in all patients), fifth finger nail/distal phalanx hypoplasia or aplasia (almost all patients at birth), and coarse facial features (commonly observed over time). Distinctive facial features include thick eyebrows and long eyelashes, broad nasal bridge, wide mouth with thick, everted upper and lower lips, and abnormal ear position or shape. Other major findings include short stature, failure to thrive, feeding difficulties, microcephaly, ophthalmological manifestations (cataracts, ptosis, strabismus), cardiac anomalies (ventricular septal/atrial septal defects, tetralogy of Fallot, patent ductus arteriosus), hypertrichosis (arms, face, back) and sparse scalp hair. Minor findings include neurologic involvement (Dandy-Walker malformation, gyral simplification, agenesis of the corpus callosum, seizures, and hypotonia), hearing loss, joint laxity, genito-urinary and renal malformations and frequent infections. Developmental delay and scoliosis appear in infancy and childhood.
Etiology
Heterozygous mutation or genomic rearrangement in the following nine genes have been reported to be causative for CSS (highest to lowest proportion of reported cases): ARID1B (6q25.3), SMARCA4 (19p13.3), SMARCC2 (12q13.2), ARID1A (1p36.11), SOX11 (2p25.2), DPF2 (11q13.1), SMARCB1 (22q11.23),SMARCE1 (17q21.2) , and ARID2 (12q12). These genes encode subunits of the BAF complex, which is involved in regulation of gene expression during development.
Diagnostic methods
To date there have been no consistent clinical criteria to assist in the diagnosis. The diagnosis is generally based on the presence of major and at least one minor clinical sign and can be confirmed by molecular genetic testing of the causative genes. Recent studies revealed that fifth finger nail/distal phalanx hypoplasia or aplasia is not a mandatory finding. Microdeletions including ARID1B have been reported.
Differential diagnosis
Differential diagnoses include Nicolaides-Baraitser syndrome, brachymorphism-onychodysplasia-dysphalangism, DOOR syndrome, hyperphosphatasia-intellectual deficiency syndrome, Borjeson-Forssman-Lehmann syndrome, Wiedemann-Steiner syndrome, Rubinstein-Taybi syndrome and Cornelia de Lange syndrome. Fetal hydantoin syndrome may mimick Coffin-Siris syndrome.
Antenatal diagnosis
As most mutations are de novo, prenatal diagnosis may be difficult to apply.
Genetic counseling
Autosomal dominant transmission has been reported regarding ARID1B-related disorder, but most cases are related to de novo mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment is essentially supportive and symptomatic. Occupational, physical and speech therapy are recommended. Development and feeding should be monitored closely and patients should undergo regular ophthalmological and audiological testing.
Prognosis
The prognosis is poor in severely affected individuals, with aspiration pneumonia and seizures reported in childhood. Association of tumor development including schwannomatosis has been reported.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Naomichi MATSUMOTO  - Dr Nobuhiko OKAMOTO


Cerebrooculofacioskeletal (COFS) syndrome is a rare genetic disorder, belonging to a family of diseases of DNA repair, characterized by a severe sensorineural involvement.

Summary:
Epidemiology
The exact incidence is unknown. To date, fewer than 20 cases have been confirmed, at a cellular or molecular level, as being truly similar to the primary cases described by Lowry, Pena and Shokeir in the indigenous population of Manitoba.
Clinical description
COFS syndrome constitutes the prenatal extreme form of Cockayne syndrome (see this term). Clinically, the following criteria are found: congenital microcephaly, congenital cataract and/or microphthalmia, arthrogryposis, severe psychomotor developmental delay, height-weight growth delay (principally postnatal) and facial dysmorphism (prominent metopic suture, micrognathism). The axial hypotonia contrasts with the peripheral hypertonia and is associated with feeding difficulties. Cutaneous photosensitivity, peripheral neuropathy, sensorineural hearing loss and pigmentary retinopathy can be observed.
Etiology
The identified mutations mainly concern the ERCC6/CSB gene. One case has been linked to the ERCC1 gene and particular clinical forms with major photosensitivity have been linked with the ERCC2/XPD and ERCC5/XPG genes. All the genes code for proteins implicated in the same route of DNA repair.
Diagnostic methods
Diagnosis is based on the evidence of a defect in DNA repair (by transcription-coupled nucleotide-excision). This anomaly can be demonstrated on fibroblasts culture by ultraviolet irradiation. Early cerebral imagery is not very specific, but it can reveal cerebral and cerebellar atrophy; myelinization anomalies and calcifications of the basal ganglia can appear secondarily.
Differential diagnosis
Differential diagnoses include infectious fetopathies (cytomegalovirus, rubella, toxoplasmosis; see these terms) and MICRO syndrome (see this term) that can present as clinically similar to COFS syndrome, but with normal DNA repair.
Antenatal diagnosis
Prenatal diagnosis can be suspected by the presence of cataract, arthrogryposis and microcephaly. It is confirmed by examination of DNA repair in chorionic villi or amniotic cells and by checking for mutations.
Genetic counseling
COFS syndrome is transmitted in an autosomal recessive manner.
Management and treatment
Management is symptomatic. Enteric feeding is often necessary.
Prognosis
COFS syndrome is a severe disease leading to death in the first years of live, particularly by respiratory infections.

                            Last update:
                            February 2009

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


COG1-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the few cases reported to date by variable signs including microcephaly, growth retardation, psychomotor retardation and facial dysmorphism.


A rare, congenital disorder of glycosylation caused by mutations in the COG2 gene and characterized by normal presentation at birth, followed by progressive deterioration with postnatal microcephaly, developmental delay, intellectual disability, seizures, spastic quadriplegia, liver dysfunction, hypocupremia and hypoceruloplasminemia in the first year of life. Diffuse cerebral atrophy and thin corpus callosum may be observed on brain MRI.


COG4-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case to date by seizures, some dysmorphic features, axial hyponia, slight peripheral hypertonia and hyperreflexia.


COG5-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case to date by moderate mental retardation with slow and inarticulate speech, truncal ataxia, and mild hypotonia.


A rare congenital disorder of glycosylation characterized by neonatal onset of global developmental delay, hypotonia, failure to thrive, hematological/immunological abnormalities, recurrent infections, liver involvement (with hepatosplenomegaly, cholestasis, fibrosis, or cirrhosis), and enteropathy. Additional reported manifestations include dysmorphic craniofacial features (such as microcephaly, broad palpebral fissures, and retrognathia), hypohidrosis, hyperkeratosis, and cardiac and musculoskeletal anomalies. Brain imaging may show hypoplastic corpus callosum, cerebral and cerebellar atrophy, and enlarged ventricles.


COG7-CDG is a congenital disorder of glycosylation characterised by dysmorphism, skeletal dysplasia, hypotonia, hepatosplenomegaly, jaundice, cardiac insufficiency, recurrent infections and epilepsy. To date, it has been described in two infants, both of whom died within the first three months of life. The syndrome is caused by a mutation in the gene encoding COG-7 (chromosome 16), a subunit of the oligomeric Golgi complex.


The CDG (Congenital Disorders of Glycosylation) syndromes are a group of autosomal recessive disorders affecting glycoprotein synthesis. CDG syndrome type IIh is characterised by severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products.

Summary:
Epidemiology
So far, only two cases have been described.
Etiology
The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.

                            Last update:
                            September 2007


A rare inflammatory/autoimmune disorder of unknown origin characterized by interstitial keratitis (IK) and audiovestibular dysfunctions.

Summary:
Epidemiology
Cogan syndrome (CS) prevalence is unknown. To date, approximately 300 cases have been reported. The disease is primarily described in causasians patients with no gender predilection.
Clinical description
CS mainly affects young adults, with a median age at onset between 20 and 30 years, and occasionally affects children. The syndrome shows a large spectrum of clinical features. Non-syphilitic IK and cochleovestibular symptoms with unilateral or bilateral sensorineural hearing loss, vertigo and tinnitus are typical CS manifestations. The interval between the onset of ocular and audio-vestibular involvement is usually less than 2 years. CS presentation is considered atypical in presence of unusual ocular involvement (such as uveitis, chronic or recurrent conjunctivitis, scleritis, optic disc edema, and retinal vasculitis, with or without IK), audiovestibular symptoms that do not resemble Menière disease, or when the latency between the two organ involvement is more than 2 years A systemic disease expression is reported in at least 1/3 of the patients, especially in atypical cases, with general symptoms such as fever, headaches, weight loss, and/or in presence of signs of organ involvement, mostly cardiovascular (aortitis, aortic insufficiency, congestive heart failure, Raynaud's phenomenon), neurological (peripheral neuropathy, meningitis, hemiparesis or hemiplegia due to a cerebral vascular accident and aphasia due to a transient ischaemic event) and gastrointestinal systems (diarrhea, melena and abdominal pains).
Etiology
CS is supposed to have an autoimmune etiology, and autoantibodies to inner ear antigens and corneal structures, such as the Cogan peptide are usually present, even if they cannot be considered specific CS serological biomarkers.
Diagnostic methods
The diagnosis is mainly clinical of exclusion of infections (in primis syphilis and Lyme disease) on the good response to corticosteroid treatment. There are no confirmatory diagnostic tests, even if laboratory tests, audiogram, and imaging may be useful for supporting the diagnosis and excluding other potential etiologies.
Differential diagnosis
Differential diagnoses include syphilis, Menière disease, Lyme disease, sarcoidosis, tuberculosis, polyarteritis nodosa, granulomatosis with polyangiitis and Takayasu arteritis.
Management and treatment
Corticosteroids are the cornerstone of CS therapy. Topical glucocorticoids in association with cycloplegics may be considered for the management of isolated, mild eye involvement, while systemic corticosteroids should be considered for more severe eye involvement, hearing impairment, and systemic manifestations. Treatment with high doses of systemic corticosteroids (1-1.5 mg/kg of prednisone daily) are expected to prevent deafness, with a beneficial response usually within 2-3 weeks. However corticosteroids have proven to be of short-term benefit, and they carry a risk of serious side effects, therefore in patients with refractory or steroid-dependent disease, a second line treatment with immunosuppressants should be considered, although conventional immunosuppressive drugs such as methotrexate, cyclophosphamide, azathioprine, or cyclosporin A seem to have a limited efficacy. There are increasing reports of successful response to Infliximab, a tumor necrosis alpha (TNFalpha) blocker. Infliximab showed cochleovestibular symptoms improvement and allowed corticosteroid tapering, with a significantly difference when compared to patients treated with steroids alone or conventional DMARDs. The early use of infliximab as first line therapy in severe cases seems to be even more effective. Cochlear implantation is a valuable rescue surgical strategy in cases of severe sensorineural hearing loss unresponsive to intensive immunosuppressive regimens.
Prognosis
The prognosis is mainly related to the risk of permanent deafness and cardiovascular complications, especially aortic insufficiency. Severe internal organ involvement and cardiovascular complications-related deaths are rare.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Rolando CIMAZ  - Dr Teresa GIANI


A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by variable iris atrophy, pigmented and pedunculated nodules on the iris and corneal abonormalities. Secondary glaucoma is also a common complication of the disease.


Cognitive impairment-coarse facies-heart defects-obesity-pulmonary involvement-short stature-skeletal dysplasia syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, short stature, skeletal abnormalities (such as brachydactyly and vertebral anomalies), obesity, cardiac, respiratory, and genitourinary anomalies, and dysmorphic facial features (including coarse facies, thick eyebrows, synophrys, hypertelorism, short, upturned nose, and long philtrum). Additional reported manifestations are microcephaly, hearing impairment, cataract, and gastroesophageal reflux.


A rare developmental defect during embryogenesis characterized by microcephaly, characteristic facial features, hypotonia, non-progressive intellectual deficit, myopia and retinal dystrophy, neutropenia and truncal obesity.

Summary:
Epidemiology
The prevalence is unknown. Approximately 200 cases have been reported to date. It is overrepresented in the Finnish population and in certain Amish, Greek/Mediterranean and Irish families.
Clinical description
Clinical manifestations seen between families are variable. At birth newborns appear normal as characteristic facial features are not yet present but neutropenia may be. The first manifestations include feeding difficulties, hypotonia, microcephaly, delayed developmental milestones (rolling over, sitting independently) and joint hypermobility. The majority of patients have a short stature with small or narrow hands and feet (compared to normal) and truncal obesity in the teen years. Characteristic facial features (high-arched or wave-shaped eyelids, thick hair, low hairline, short philtrum as well as long-thick eyelashes, prominent nasal root and upper central incisors) start to appear around the age of 5 and become more evident between the ages of 7-14 and into adulthood. Speech development is delayed. Aphthous ulcers are present in some. Recurrent upper respiratory infections are also seen in certain patients, possibly due to neutropenia. Intellectual deficiency is noted but is not progressive and the learning of new concepts is possible. Patients are often very sociable with a cheerful disposition. In adolescence, myopia and strabismus are present along with signs of retinochoroidal dystrophy in most cases. Nyctalopia and a narrowed visual field develop with time, and vision progressively begins to deteriorate after the age of 30. Patients over 45 suffer from severe retinochoroidal atrophy and posterior subcapsular cataracts. Although visual abnormalities are severe they do not lead to blindness.
Etiology
CS is caused by a mutation in the vacuolar protein sorting 13B (VPS13B) gene on locus 8q22-8q23 which is thought to have a role in vesicle mediated sorting and intracellular protein trafficking. More than 100 different null mutations (resulting in the truncation of the final protein) have been identified in the gene.
Diagnostic methods
Characteristic clinical findings along with molecular genetic testing for the presence of mutations in the VPS13B gene are required for a definite diagnosis of CS.
Differential diagnosis
Differential diagnoses include Bardet-Biedl syndrome, Prader-Willi syndrome, Cri-du-chat syndrome, Alström syndrome, Angelman syndrome, Williams syndrome, MORM syndrome and monosomy 1p36 (see these terms). Mirhosseini-Holmes-Walton syndrome is considered allelic to CS and is clinically indistinguishable.
Antenatal diagnosis
Antenatal diagnosis is possible if mutations in family members have been identified.
Genetic counseling
CS is transmitted autosomal recessively and genetic counseling is recommended for at-risk individuals.
Management and treatment
Spectacles/eyeglasses are necessary. Intellectual deficiency requires special education and children often attend specialized schools. Speech therapy is important during the preschool years to foster speech development as well as physical therapy for motor delay, hypotonia and motor clumsiness. Respiratory infections should be treated with antibiotics. Granulocyte-colony stimulating factor (G-CSF) has been given to some patients to treat neutropenia. Ophthalmologic evaluation is needed to determine visual acuity. No effective treatment has been developed to halt the progression of the retinal disease. In later years, training for the visually impaired can be offered. Psychosocial support should be offered to patients and their families.
Prognosis
There is no evidence of the decrease in life expectancy but quality of life is reduced due to visual impairment.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Heng WANG


COL4A1/2-related familial vascular leukoencephalopathy

A rare genetic neurological disorder characterized by the presence of fragile small-vessel intracerebral vasculature in various members of a single family, manifesting, clinically, with single or recurrent hemorrhagic and/or ischemic stroke and, frequently, ocular and renal involvement. Neuroimaging reveals diffuse, periventricular leukoencephalopathy associated with dilated perivascular spaces, lacunar infarction and microhemorrhages.


Colchicine poisoning is a potentially life-threatening poisoning, due to ingestion of the drug or consumption of the plant Colchicum autumnale, that usually begins with gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting, and diarrhea, that cause severe dehydration) and an initial leukocytosis leading to marrow failure (24 hours after ingestion), followed by potentially fatal multi-organ failure with mental status change, oliguric renal failure, disseminated intravascular coagulation, electrolyte imbalance, acid-base disturbance, cardiac failure/arrest and shock within 1-3 days.


Cold agglutinin disease is a type of autoimmune hemolytic anemia (see this term) defined by the presence of cold autoantibodies (autoantibodies which are active at temperatures below 30°C).

Summary:
Epidemiology
Cold agglutinin disease represents an estimated 16-32% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.
Clinical description
It occurs more frequently after the age of 55. Cold agglutinin disease manifests as acute or chronic hemolytic anemia, with associated pallor and fatigue. Symptoms during hemolytic ``crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly. A cold environment or a concurrent infection may trigger or exacerbate the condition, and episodes of acute hemolysis with hemoglobinemia and hemoglobinuria are more common in winter. The disease may appear abruptly with anemia and hemoglobinuria, or onset may be more gradual and insidious.
Etiology
Cold agglutinin disease can be primary (idiopathic) or secondary, caused by an underlying condition, such as infection (Mycoplasma pneumoniae), lymphoproliferative disorders, systemic autoimmunity or neoplasm. The majority of cold agglutinin disease is secondary and is due to the presence of monoclonal IgM (kappa subtype in the majority of the cases), which has the properties of a cold agglutinin and is associated with an underlying low-grade B-cell lymphoma (Waldenström macroglobulinemia or lymphocytic lymphoma; see these terms). Idiopathic and lymphoma-associated cold AIHA tend to be chronic while infections tend to cause an acute disease.
Diagnostic methods
In some cases, the diagnosis is made by chance on a standard complete blood count (CBC) detecting abnormal agglutination of the red blood cells. Diagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, specifically IgM, with the direct anti-globulin test (DAT, C3 positive pattern) with the presence of circulating cold agglutinins inthe serum. In secondary cases, lymphocytosis, with the presence of atypical lymphocytes on the smear, can be found in peripheral blood.
Differential diagnosis
The differential diagnosis for cold agglutinin disease is mixed AIHA (see this term).
Management and treatment
Patients with few clinical symptoms and mild anemia may not require treatment but only avoidance of cold. Keeping the patient warm may be sufficient treatment. The disease is usually refractory to corticosteroids. Rituximab may be an option for treatment in some cases. In the presence of underlying lymphoma, chlorambucil or oral cyclophosphamide may be helpful.
Prognosis
The disease has a chronic course and the outcome is usually benign, except in patients with recurrent episodes of severe anemia or in whom the underlying B-cell lymphoma has an aggressive course.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


Cold-induced sweating syndrome (CISS) is characterized by profuse sweating (involving the chest, face, arms and trunk) induced by cold ambient temperature.

Summary:
Epidemiology
So far, six cases have been reported of Norwegian, Israeli and Canadian origin.
Clinical description
Additional abnormalities may include kyphoscoliosis, a high-arched palate, a nasal voice, depressed nasal bridge, and impaired peripheral sensitivity to pain and temperature.
Etiology
CISS is caused by mutations in the CRLF1 gene on chromosome 19p12 (CISS type 1). In one Australian man with no family history, the syndrome was associated with mutations in the CLCF1 gene on chromosome 11q13.3 (CISS type 2).
Genetic counseling
CISS is an autosomal recessive disorder.

                            Last update:
                            February 2009


An extremely rare form of bone dysplasia characterized by the features of osteogenesis imperfecta such as bone fragility associated with multiple fractures, bone deformities (metaphyseal irregularities and bowing of the long bones) and blue sclera, in association with growth failure, craniosynostosis, hydrocephalus, ocular proptosis, and distinctive facial features (e.g. frontal bossing, midface hypoplasia, and micrognathia).


A rare non-immune-mediated glomerular disease characterized by abnormal accumulation of type III collagen within the mesangium and subendothelial space of the glomerulus. Clinically it usually manifests with proteinuria (often in the nephrotic range), microscopic hematuria, peripheral edema and/or hypertension. Progression to end-stage kidney failure is possible.

Summary:
Epidemiology
Approximately 100 cases have been reported worldwide. Most have been from Japan, where it was first described, though subsequently cases from China, the Indian subcontinent, Europe, North and South America. No definitive variation in penetrance by sex has been described.
Clinical description
The disorder typically presents as an adult onset nephrotic syndrome with hypertension, anemia and microangiopathic hemolytic anemia that may appear to be a hemolytic uremic syndrome (HUS). Presentations in pediatric patients is rare and typically associated with familial occurrence. There is some evidence that it may present as a systemic disease including with partial villous atrophy of the intestine, hepatic perisinusoidal fibrosis and on autopsy accumulation of collagen III in spleen, liver, myocardium, and thyroid gland has been reported.
Etiology
The etiology has not been established.
Diagnostic methods
Renal biopsy shows glomerular basement membrane double contours without hypercellularity, expansion of subendothelial space and mesangium that is birefringent on picrosirius red staining and negative on silver and congo red stains, and ultrastructural evidence of type III collagen fibers (40-65 nm). Immunostaining with antibodies for anti-Collagen III shows strong staining. Serum analysis will demonstrate increased procollagen III peptide (PIIIP) levels. There are reports of elevated serum hyaluronan levels (1000x normal). A rare case of full house staining and coincident diabetes in a pediatric patient has been reported. In one case where serial biopsies were available, the collagenofibrotic pattern evolved from more typical focal segmental glomerulosclerosis (FSGS). One patient with Hodkin lymphoma was reported to have co-incident collagenofibrotic glomerulopathy.
Differential diagnosis
Differential diagnosis includes nail-patella syndrome (an LMX1B-associated nephropathy where the lamina densa is not spared on ultrastructural examination), fibrillar collagen in glomerulosclerosis or in diabetic glomerulopathy (diabetic fibrillosis which is segmental with sparing of subendothelial space), fibronectin glomerulopathy (less fibrilar and not banded), Amyloidosis (straight, small, non-banded fibrils that are Congo red positive).
Genetic counseling
Genetic testing of LMX1B to exclude nail-patella syndrome is necessary, though a cases of renal limited LMX1B nephropathy has been identified. Familial occurrence in young patients, including in siblings, suggests autosomal recessive inheritance with adult onset cases more likely to be sporadic. Co-occurrence of an inherited Factor H deficiency has been reported.
Management and treatment
Definitive treatments, including renal transplantation, have not been established. A report of angiotensin II blocker (telmisartan) with improvement in clinical signs and symptoms, albeit with no significant change in laboratory findings, has been reported.
Prognosis
The disorder can be insidious with variable progression to end stage renal disease within 10 years. While no reports of recurrence following transplantation are reported, there is one case where PIIIP levels were elevated in a patient post-transplantation suggesting a risk for recurrence, and one de novo case occurring following a renal transplant.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Avi ROSENBERG


Collecting duct carcinoma is a rare, aggressive subtype of renal cell carcinoma, which originates from the epithelium of the distal collecting ducts, and usually manifests with hematuria, flank pain, palpable abdominal mass or nonspecific symptoms, such as fatigue, weight loss or fever. Patients are often asymptomatic for long periods of time and therefore, disease is often locally advanced or metastatic at the time of diagnosis. In cases with metastatic spread, bone pain, cough, dyspnea, pneumonia or neurological compromise may be associated.


Coloboma of choroid and retina is a rare, genetic developmental defect during embryogenesis characterized by the partial absence of retinal pigment epithelium and choroid, most frequently located in the inferonasal quadrant. Patients usually present reduced vision and have an increased risk for retinal detachment. Other ocular anomalies (e.g. coloboma of iris, microcornea, nystagmus, strabismus, microphthalmos) are usually associated, however it may also be isolated.


A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral abnormal lens shape (contraction of the lens with a notch) due to segmentally defective, or absent, development of the zonule and flattening of the equator in the region of the zonular defect, typically manifesting with reduced visual acuity. Other ocular anomalies, such as iris, choroid or optic disc colobomas, as well as cataracts and retinal detachment, may be associated.


A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral, symmetrical or asymmetrical, partial or full thickness defect of the superior or inferior eyelid margin, ranging in size from a small notch to complete absence of the entire lid, typically located on the medial to lateral third of the eyelid, resulting in an unprotected cornea and thus possibly leading to exposure keratopathy and vision impairment. It may occur isolated, be associated with other ocular defects or be part of a craniofacial syndrome, such as Treacher-Collins or Goldenhar syndrome.


Coloboma of inferior eyelid is a rare developmental defect during embryogenesis characterized by a unilateral or bilateral, partial or full-thickness, variably sized defect of the inferior eyelid (ranging from a small notch to complete absence of the entire lid) which is usually triangular in shape (with base at eyelid margin) and located on the lateral third of the lid. It can occur isolated, associated with facial clefting or as part of a syndrome.


A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral notch, gap, hole or fissure, typically located in the inferonasal quadrant of the eye, involving only the pigment epithelium or the iris stroma (incomplete) or involving both (complete), manifesting with iris shape anomalies (e.g. 'keyhole' or oval pupil) and/or photophobia. Association with colobomata in other parts of the eye (incl. ciliary body, zonule, choroid, retina, optic nerve) and complex malformation syndromes (such as CHARGE syndrome) may be observed.


Coloboma of macula-brachydactyly type B syndrome

A rare congenital malformation syndrome characterized by the combination of bilateral coloboma of macula with horizontal pendular nystagmus and severe visual loss, and brachydactyly type B. The hand and feet defects comprise of shortening of the middle and terminal phalanges of the second to fifth digits, hypoplastic or absent nails (congenital anonychia), broad or bifid thumbs and halluces, syndactyly and flexion deformities of the joints of some digits.


Coloboma of macula is a rare, non-syndromic developmental defect of the eye characterized by well-circumscribed, oval or rounded, usually unilateral, atrophic lesions of varying size presenting rudimentary or absent retina, choroid and sclera located at the macula leading to decreased vision and, on occasion, other symptoms (e.g. strabismus). It is usually isolated, but may also be associated with Down syndrome, skeletal or renal disorders.


Coloboma of optic disc is a rare, genetic, developmental defect of the eye characterized by a unilateral or bilateral, sharply demarcated, bowl-shaped, glistening white excavation on the optic disc (typically decentered inferiorly) which usually manifests with varying degrees of reduced visual acuity. It can occur isolated or may associate other ocular (e.g. retinal detachment, retinoschisis-like separation) or systemic anomalies (e.g. renal).


Coloboma of superior eyelid is a rare developmental defect during embryogenesis characterized by a typically unilateral, partial or full-thickness, variably sized defect of the superior eyelid, ranging from a small notch to complete absence of the entire lid, which is commonly triangular in shape (with base at eyelid margin) and located on the medial third of the lid. It can occur isolated, associated with other anomalies (e.g. ocular/orbital and facial), or as part of a syndrome.


A rare genetic eye disease characterized by microcornea, coloboma of the iris and the optic disc, axial enlargement of the globe, staphyloma, and severe myopia. Additional manifestations are mild cornea plana, iridocorneal angle abnormalities with elevation of intraocular pressure, and shallow anterior chamber depth. Variable expressivity of the phenotype has been described, including unilateral or bilateral involvement, or variable extent of coloboma, among other features.


Colobomatous microphthalmia-obesity-hypogenitalism-intellectual disability syndrome

A rare syndromic microphthalmia characterized by bilateral, usually asymmetrical, microphthalmia associated typically with a unilateral coloboma, truncal obesity, borderline to mild intellectual disability, hypogenitalism and, more variably, nystagmus, cataracts and developmental delay.


Colobomatous microphthalmia-rhizomelic dysplasia syndrome is a rare, genetic developmental defect during embryogenesis characterized by a range of developmental eye anomalies (including anophthalmia, microphthalmia, colobomas, microcornea, corectopia, cataract) and symmetric limb rhizomelia with short stature and contractures of large joints. Intellectual disability with autistic features, macrocephaly, dysmorphic features, urogenital anomalies (hypospadia, cryptorchidism), cutaneous syndactyly and precocious puberty may also be present.


Colobomatous microphthalmia is a developmental disorder of the eye characterized by unilateral or bilateral microphthalmia associated with ocular coloboma.


Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

A rare genetic eye disease characterized by optic disc anomalies (bilateral colobomatous optic discs, retinal vessels arising from the peripheral optic disc) and macular atrophy. Peripapillary chorioretinal atrophy and chorioretinal and iris coloboma have also been described. Patients present with horizontal nystagmus and poor visual acuity.


Colonic atresia is a congenital intestinal malformation resulting in a non-latent segment of the colon and characterized by lower intestinal obstruction manifesting with abdominal distention and failure to pass meconium in newborns.


An acute arboviral infection caused by a Coltivirus transmitted by an infected tick and characterized by a biphasic fever with headache, myalgias, arthralgias, and fatigue that can last 3 weeks or more. In some cases, macular, maculopapular, or petechial rash and/or stiff neck, nausea, vomiting, abdominal pain, diarrhea, and sore throat may also occur.


A rare inherited bleeding disorder due to the reduction in activity and antigen levels of both factor V (FV) and factor VIII (FVIII) and characterized by mild-to-moderate bleeding symptoms.

Summary:
Epidemiology
Prevalence is estimated between 1/100,000 and 1/1,000,000. The condition is more prevalent in the Mediterranean area and in areas where consanguineous marriages are common.
Clinical description
Combined FV and FVIII deficiency can manifest at any age. Epistaxis, easy bruising, post-surgical or post partum bleeding and menorrhagia are the most common symptoms. Hemarthrosis and muscular hematomas may occur. The symptoms are usually mild.
Etiology
Combined deficiency of factor V and factor VIII is caused by mutations either in the LMAN1 gene (chromosome 18; 18q21) or in the MCFD2 gene (chromosome 2; 2p21). LMAN1 encodes ERGIC-53, a transmembrane lectin, while MCFD2 is an EF-hand-containing protein. The ERGIC-53/MCFD2 protein complex functions as a cargo receptor that facilitates the transport of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi apparatus. Mutations in LMAN1 account for approximately 70% of cases and include only null mutations. Mutations in MCFD2 account for approximately 30% of cases and include both null and missense mutations.
Diagnostic methods
Diagnosis is based on the measurement of factor V and factor VIII levels and on the detection of prolonged activated partial thromboplastin and prothrombin times. Levels of factor V and factor VIII range from as low as 1% to as high as 46%, but generally fall between 5% and 30%.
Differential diagnosis
Differential diagnosis includes co-inheritance of both FV deficiency (chromosome 1) and FVIII deficiency (chromosome X).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management aims at controlling the bleeding and includes treatments with fresh frozen plasma, FVIII concentrates and desmopressin administration.
Prognosis
The prognosis is favorable for moderate forms of the disease. Management of patients with more severe forms should be carried out at a specialized center.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Combined hamartoma of the retina and retinal pigment epithelium

A rare benign eye tumor characterized by the presence of glial cells, vascular tissue, and sheets of pigment epithelial cells lacking the distribution and organization of the normal retina and retinal pigment epithelium. The lesion is most commonly found unilaterally as a slightly elevated mass in a peripapillary location but can also occur in the macula or the retinal periphery. It is sometimes associated with neurofibromatosis type 1 or 2, nevoid basal cell carcinoma syndrome, or branchio-oculo-facial syndrome. Patients may be asymptomatic or present with progressive loss of vision.


Combined hepatocellular carcinoma and cholangiocarcinoma

A rare hepatic tumor characterized by the presence of both hepatocytic and cholangiocytic differentiation within a primary liver carcinoma. The lesion commonly arises in the context of chronic liver disease (such as hepatitis B or C, or steatohepatitis) or exposure to a variety of exogenous agents. Patients may present with signs and symptoms related to the tumor, as well as to the underlying condition. Typical manifestations include right upper quadrant abdominal pain, weight loss, hepatosplenomegaly, jaundice, and ascites. The entity has been associated with a worse prognosis than hepatocellular carcinoma after resection.


Combined hyperactive dysfunction syndrome of the cranial nerves

A rare, acquired peripheral neuropathy characterized by symptoms arising from combined overactivity in cranial nerves, without any explanatory structural lesion. The symptoms may be unilateral or bilateral, may occur synchronously or metachronously, and include trigeminal neuralgia, hemifacial spasm and glossopharyngeal neuralgia.


Combined immunodeficiency due to CARD11 deficiency

Severe combined immunodeficiency due to CARD11 deficiency is a rare combined T and B cell immunodeficiency characterized by normal numbers of T and B lymphocytes, increased numbers of transitional B cells and hypo- to agammaglobulinemia, decreased numbers of regulatory T cells and defects in T-cell functions. It presents with severe susceptibility to infections, including opportunistic infections.


Combined immunodeficiency due to CARMIL2 deficiency

A rare immune dysregulation disease with immunodeficiency characterized by infantile or childhood onset of a variable phenotype including recurrent/persistent bacterial, fungal, and viral infections with involvement of the skin, lower respiratory tract, and gastrointestinal tract, eczema, allergies, and inflammatory bowel disease, among others. EBV-related smooth muscle tumors have also been reported. Immunophenotyping shows decreased Treg counts, as well as a deficient CD3/CD28 co-stimulation response in CD4+ and CD8+ T-cells.


Combined immunodeficiency due to CD27 deficiency

A rare autosomal recessive primary immunodeficiency characterized by Epstein-Barr virus (EBV)-triggered lymphoprolipherative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma and EBV-driven hemophagocytic lymphohistiocytosis (HLH). Aplastic anemia and inflammatory disorders such as uveitis and oral ulcers are also observed.


Combined immunodeficiency due to CD3gamma deficiency

A rare autosomal recessive primary immunodeficiency characterized by partial T lymphopenia (in particular cytotoxic CD8+ cells) and decreased expression of the T cell receptor (TCR)/CD3 complex with impaired proliferative response to TCR-dependent stimuli, while the mature memory T cell pool is comparatively well preserved, and B cells, natural killer cells, and immunoglobulins are typically normal. The clinical phenotype is highly heterogeneous, ranging from asymptomatic to infancy-onset of severe recurrent infections, as well as occurrence of autoimmune disease or enteropathy.


Combined immunodeficiency due to CD70 deficiency

A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-related disorders (B-cell lymphoproliferative disorders including Hodgkin lymphoma) as well as dysgammaglobulinemia and recurrent infections. Patients can present with recurrent fever, lymphadenopathy, hepatosplenomegaly, Behçet-like stomatitis, pharyngitis, tonsillitis, adenitis, and viral encephalitis.


Combined immunodeficiency due to CRAC channel dysfunction

Combined immunodeficiency (CID) due to Ca2+ release activated Ca2+(CRAC) channel dysfunction is a form of CID characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia. It comprises two sub-types that are due to mutations in the ORAI1 and STIM1 genes: CID due to ORAI1 deficiency and CID due to STIM1 deficiency.

Summary:
Epidemiology
CID due to CRAC channel dysfunction has been reported in 10 patients from 5 families, 6 patients in 3 families with ORAI1 mutations and 4 patients in two families with STIM1 mutations.
Clinical description
CID due to CRAC channel dysfunction is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy, which is characterized by non-progressive generalized muscular dysplasia. For cases with ORAI1 mutations this presents as poor head control after birth, delayed ambulation and a positive Gower's sign, while patients with STIM1 mutations present with global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients with ORAI1 mutations also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation. Patients with STIM1 mutations also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia.
Etiology
CID due to CRAC channel dysfunction is caused by mutations in the ORAI1 and STIM1 genes (12q24 and 11p15.5).
Diagnostic methods
Diagnosis is based on clinical features and testing the function and proliferation of T cells. Patients have normal lymphocyte counts and serum immunoglobulin levels but severely compromised T cell activation.
Differential diagnosis
Differential diagnoses include combined immunodeficiency (CID) due to ZAP70 deficiency, CID due to CD3gamma deficiency, immunodeficiency due to CD25 deficiency, hypohidrotic ectodermal dysplasia with immunodeficiency and anhidrotic ectodermal dysplasia - immunodeficiency - osteopetrosis - lymphedema syndrome.
Antenatal diagnosis
Prenatal diagnosis can be performed where there is a family history and where the genetic mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment with hematopoietic stem cell transplantation (HSCT) has been successful in some cases.
Prognosis
Without treatment, patients fail to thrive and die in their first year of life.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Combined immunodeficiency due to DOCK2 deficiency

A rare, primary combined T and B cell immunodeficiency characterized by early-onset of recurrent, invasive viral and bacterial infections associated with T and B cell lymphopenia, functional defects in T and B cells, poor antibody response and thrombocytopenia. Depending on the type of infectious agent, variable clinical manifestations commonly include recurrent pneumonia, bronchiolitis, otitis media, meningoencephalitis, colitis, and diarrhea, leading to fatal multiorgan failure in severe cases.


Combined immunodeficiency due to DOCK8 deficiency

Combined immunodeficiency due to dedicator of cytokinesis 8 protein (DOCK8) deficiency is a form of T and B cell immunodeficiency characterized by recurrent cutaneous viral infections, susceptibility to cancer and elevated serum levels of immunoglobulin E (IgE).

Summary:
Epidemiology
Prevalence is unknown. To date, 11 patients in eight families have been reported.
Clinical description
Patients present in childhood with symptoms including atopic dermatitis, severe food and environmental allergies, asthma, recurrent upper and lower respiratory tract infections including otitis media, recurrent sinusitis, bronchitis and pneumonia, and extensive cutaneous viral and bacterial infections including superficial, often ulcerating herpes simplex virus infections, flat and verrucous warts, molluscom contagiosum infections, S. aureus skin infections or abscesses, mucosal or nail candidiasis and otitis externa. Patients with long-term herpes simplex virus infections, human papillomavirus infections or molluscom contagiosum have developed vulvar, facial and anal squamous cell dysplasia and carcinoma. The neurologic, vasculitic and autoimmune symptoms associated with autosomal dominant hyper IgE syndrome due to mutations in STAT3 (see this term), are not observed.
Etiology
CID due to DOCK8 deficiency is caused by homozygous or compound heterozygous deletions and point mutations in the DOCK8 gene (9p24), which leads to an absence of DOCK8 protein in lymphocytes, resulting in low absolute T and B lymphocyte counts, mild-to-moderate eosinophilia and very high levels of serum IgE.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Combined immunodeficiency due to GINS1 deficiency

A rare syndrome with combined immunodeficiency characterized by intrauterine and postnatal growth retardation, chronic neutropenia, and natural killer (NK) cell deficiency due a defect in DNA replication leading to blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells. Other clinical features include recurrent viral and bacterial infections and eczema, as well as mild facial dysmorphism.


Combined immunodeficiency due to IL21R deficiency

A rare, genetic, non-severe combined immunodeficiency disorder characterized by variable B- and T-cell defects (including defective B-cell differentiation and impaired T-cell proliferation to mitogens and bacterial antigens) and natural killer cell dysfunction (ranging from impaired cytotoxicity to lymphopenia) due to IL21R deficiency, manifesting with recurrent respiratory and/or gastrointestinal tract infections and, in some cases, with severe, chronic, progressive cholangitis and liver cirrhosis associated with cryptosporidial infection.


Combined immunodeficiency due to ITK deficiency

A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-associated lymphoproliferative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma, lymphoid granulomatosis, hemophagocytic lymphohistiocytosis, and smooth muscle tumor. Patients present persistent symptoms of infectious mononucleosis including recurrent febrile episodes, lymphadenopathies, and hepatosplenomegaly, accompanied by high EBV viral load in the blood. Additional manifestations are autoimmune diseases like hemolytic anemia or renal disease.


Combined immunodeficiency due to LRBA deficiency

A rare, genetic, primary immunodeficiency characterized by early onset of recurrent respiratory infections and variable combination of autoimmune disorders, including hemolytic anemia, thrombocytopenic purpura, lymphoproliferative disease, inflammatory bowel disease, colitis, diabetes, arthritis, and dermatitis. Failure to thrive, hepatosplenomegaly and endocrine abnormalities have also been associated. Variable immunologic findings include deficiency of CD4+ T regulatory cells, decreased B-cells, and hypogammaglobulinemia.


Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.


Combined immunodeficiency due to Moesin deficiency

A rare combined T and B cell immunodeficiency characterized by childhood onset of recurrent bacterial and varicella zoster virus infections. Eczema and recurrent molluscum have also been reported. Laboratory studies reveal profound and persistent lymphopenia, hypogammaglobulinemia, poor immune response to vaccine antigens, and fluctuating neutropenia.


Combined immunodeficiency due to ORAI1 deficiency

Combined immunodeficiency (CID) due to ORAI1 deficiency is a form of CID due to Calcium release activated Ca2+ (CRAC) channel dysfunction (see this term) characterized by recurrent infections, congenital myopathy, ectodermal dysplasia and anhydrosis.

Summary:
Epidemiology
To date, it has been reported in 6 patients in 3 families.
Clinical description
The disease is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as poor head control after birth, delayed ambulation and a positive Gower's sign. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation.
Etiology
The disease is caused by mutations in the ORAI1 gene (12q24.31) which codes for calcium release-activated calcium channel protein 1.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Combined immunodeficiency due to OX40 deficiency is a rare combined T and B cell immunodeficiency characterized by susceptibility to develop an aggressive, childhood-onset, disseminated, cutaneous and systemic Kaposi sarcoma.


Combined immunodeficiency due to partial RAG1 deficiency is a form of combined T and B cell immunodeficiency (CID; see this term) characterized by severe and persistent cytomegalovirus (CMV) infection and autoimmune cytopenia.

Summary:
Epidemiology
Prevalence is unknown. To date, 9 cases have been reported.
Clinical description
Patients present before the age of one year with severe disseminated CMV infection, which can manifest with fever and splenomegaly, and recurrent and severe co-infections including sepsis and pneumonitis. Autoimmune cytopenia also occurs and can include autoimmune hemolytic anemia (see these terms) or neutropenia.
Etiology
SCID due to partial RAG1 deficiency is caused by hypomorphic mutation in the RAG1 gene (11p13). This results in oligoclonal expansion of T cell receptor (TCR) gamma-delta T cells and TCR alpha-beta T cell lymphopenia, although total lymphocyte counts are normal, in combination with CMV infection and autoimmunity.
Diagnostic methods
Diagnosis is based on clinical evaluation, immunological investigation, including lymphocyte subset phenotyping, lymphocyte proliferation to mitogen stimulation, immunoglobulin levels and antibody response to vaccine antigens, and genetic confirmation.
Differential diagnosis
Differential diagnoses include other combined immunodeficiencies.
Antenatal diagnosis
Prenatal diagnosis can be performed in families where there is a family history and in which the genetic mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment involves antiviral treatment and management of recurrent infections. Bone marrow transplant has been attempted but may result in graft versus host disease (GVHD; see this term) associated with reactivation of CMV disease. Patients should be treated in centers with experience of transplanting complex primary immunodeficiencies.
Prognosis
The majority of patients reported to date have died within the first few years of life.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Combined immunodeficiency due to RELA haploinsufficiency

A rare non-severe combined immunodeficiency characterized by TNF-dependent chronic mucocutaneous ulcerations and inflammatory bowel disease presenting during the first years of life. Ulcerations occur primarily in the oral, gastrointestinal, and vaginal mucosa.


Combined immunodeficiency due to STIM1 deficiency

Combined immunodeficiency (CID) due to STIM1 deficiency is a form of CID due to Calcium release activated Ca2+(CRAC) channel dysfunction (see this term) characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia.

Summary:
Epidemiology
To date, it has been reported in 4 patients from two families.
Clinical description
CID due to STIM1 deficiency is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia (see these terms).
Etiology
The disease is caused by mutations in the STIM1 gene (11p15.5) which codes for stromal interaction molecule 1.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Combined immunodeficiency due to STK4 deficiency

A rare, genetic, combined T and B cell immunodeficiency characterized by T- and B-cell lymphopenia, hypergammaglobulinemia and intermittent neutropenia. It presents with recurrent opportunistic viral, bacterial and fungal infections involving skin (cutaneous papillomatosis, molluscum contagiosum, skin abscesses, mucocutaneous candidiasis), upper and lower respiratory tract or septicemia. Other clinical features include autoimmune manifestations (autoimmune hemolytic anemia) and congenital heart defects (atrial septal defects, patent foramen ovale, mitral, triscupid and pulmonary valve insufficiency).


Combined immunodeficiency due to TFRC deficiency

A rare genetic combined T and B cell immunodeficiency characterized by life-threatening infections due to disrupted transferrin receptor 1 endocytosis, resulting in defective cellular iron transport and impaired T and B cell function. Patients present with early-onset chronic diarrhea, severe recurrent infections, and failure to thrive. Laboratory studies reveal hypo- or agammaglobulinemia, normal lymphocyte counts but decreased numbers of memory B cells, intermittent neutropenia and thrombocytopenia, and mild anemia (resistant to iron supplementation) with low mean corpuscular volume.


Combined immunodeficiency due to ZAP70 deficiency

A very rare, severe, genetic, combined immunodeficiency disorder characterized by lymphocytosis, decreased peripheral CD8+ T-cells, and presence of normal circulating CD4+ T-cells, leading to immune dysfunction.


Combined immunodeficiency with facio-oculo-skeletal anomalies

A rare combined immunodeficiency disorder characterized by primary immunodeficiency manifesting with repeated bacterial, viral and fungal infections, in association with neurological manifestations (hypotonia, cerebellar ataxia, myoclonic seizures), developmental delay, optic atrophy, facial dysmorphism (high forehead, hypoplastic supraorbital ridges, palpebral edema, hypertelorism, flat nasal bridge, broad nasal root and tip, anteverted nares, thin lower lip overlapped by upper lip, square chin) and skeletal anomalies (short metacarpals/metatarsals with cone-shaped epiphyses, osteopenia).


Combined immunodeficiency with granulomatosis

A rare, genetic, non-severe combined immunodeficiency disease characterized by immunodeficiency (manifested by recurrent and/or severe bacterial and viral infections), destructive noninfectious granulomas involving skin, mucosa and internal organs, and various autoimmune manifestations (including cytopenias, vitiligo, psoriasis, myasthenia gravis, enteropathy). Immunophenotypically, T-cell and B-cell lymphopenia, hypogammaglobulinemia, abnormal specific antibody production and impaired T-cell function are observed.


A rare genetic disease characterized by multiple intestinal atresia in association with combined immunodeficiency and inflammatory bowel disease. Clinical features include widespread atresia extending from the stomach to the rectum, homogenous calcifications in the abdominal cavity, hepatic cholestasis, cirrhosis, and chronic liver failure, hypoplastic thymus, and increased susceptibility to mainly bacteria and viruses. The immunological phenotype consists of profound generalized T-cell lymphopenia and milder natural killer cell and B-cell lymphopenia, as well as low serum levels of IgG, IgA, and IgM, with elevated serum IgE. The disease is mostly fatal in infancy or childhood.


Combined malonic and methylmalonic acidemia

A rare inborn error of metabolism characterized by elevation of malonic acid (MA) and methylmalonic acid (MMA) in body fluids, with higher levels of MMA than MA. CMAMMA presents in childhood with metabolic acidosis, developmental delay, dystonia and failure to thrive or in adulthood with seizures, memory loss and cognitive decline.


Combined oxidative phosphorylation defect type 11

A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype which ranges from a fatal neonatal/infantile encephalomyopathy with lactic acidosis, hyporeflexia/areflexia, severe hypotonia and respiratory failure to less severe cases presenting with central hypotonia, global developmental delay, congenital sensorineural hearing loss, and renal disease. Additional, variably observed, clinical features include intellectual disability, seizures, and cardiomyopathy.


Combined oxidative phosphorylation defect type 13 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by normal early development followed by the sudden onset in infancy of poor feeding, dysphagia, truncal (followed by global) hypotonia, motor regression, abnormal movements (i.e. severe dystonia of limbs, choreoathetosis, facial dyskinesias) and reduced tendon reflexes. The disease course is severe but nonprogressive.


Combined oxidative phosphorylation defect type 14 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by neonatal or infancy-onset of seizures that are refractory to treatment, delayed or absent psychomotor development and lactic acidosis. Additional manifestations reported include poor feeding, failure to thrive, microcephaly, hypotonia, anemia and thrombocytopenia.


Combined oxidative phosphorylation defect type 15 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported.


Combined oxidative phosphorylation defect type 17 is a rare, genetic, mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by infantile-onset of severe hypertrophic cardiomyopathy (that occasionally progresses to dilated cardiomyopathy) associated with failure to thrive, global development delay, muscular hypotonia, elevated serum lactate and complex I deficiency in skeletal muscle biopsy. Intellectual disability, pericardial effusion and a mild cardiac phenotype have been also reported.


Combined oxidative phosphorylation defect type 2 is a rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by severe intrauterine growth retardation, neonatal limb edema and redundant skin on the neck (hydrops), developmental brain defects (corpus callosum agenesis, ventriculomegaly), brachydactyly, dysmorphic facial features with low set ears, severe intractable neonatal lactic acidosis with lethargy, hypotonia, absent spontaneous movements and fatal outcome. Markedly decreased activity of complex I, II + III and IV in muscle and liver have been determined.


Combined oxidative phosphorylation defect type 20

A rare mitochondrial oxidative phosphorylation disorder characterized by variable combination of psychomotor delay, hypotonia, muscle weakness, seizures, microcephaly, cardiomyopathy and mild dysmorphic facial features. Variable types of structural brain anomalies have also been reported. Biochemical studies typically show decreased activity of mitochondrial complexes (mainly complex I).


Combined oxidative phosphorylation defect type 21 is a rare mitochondrial disease characterized by axial hypotonia with limb hypertonia, developmental delay, hyperlactatemia, central nervous system anomalies visible on magnetic resonance imaging (e.g. corpus callosum hypoplasia, lesions of the globus pallidus) and multiple deficiency of the mitochondrial respiratory chain complexes in muscle tissue, but not in fibroblasts or liver.


Combined oxidative phosphorylation defect type 23

A rare mitochondrial disease characterized by early onset of hypertrophic cardiomyopathy and variable neurologic symptoms including global developmental delay, hypotonia, intellectual disability, visual impairment, and seizures. Lactic acidosis is present in all patients. Muscle biopsy usually shows decreased activity of mitochondrial complexes I and IV. Brain imaging may reveal variable abnormal signal intensities in the thalamus, basal ganglia, and/or brain stem.


Combined oxidative phosphorylation defect type 24 is a rare mitochondrial oxidative phosphorylation disorder characterized by variable phenotype, including developmental delay with psychomotor regression, intellectual disability, epilepsy, Leigh syndrome, non-syndromic hearing loss, visual impairment and severe myopathy. Decreased activity of mitochondrial respiratory complexes and lactic acidosis are common findings, and diffuse cerebral atrophy may be associated.


Combined oxidative phosphorylation defect type 25 is a rare mitochondrial oxidative phosphorylation disorder with decreased respiratory complex I and IV enzyme activities, characterized by hypotonia, global developmental delay, neonatal onset of progressive pectus carinatum without other skeletal abnormalities, poor growth, sensorineural hearing loss, dysmorphic features and brain abnormalities such as cerebral atrophy, quadriventricular dilatation and thin corpus callosum posteriorly.


Combined oxidative phosphorylation defect type 26

A rare mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype which may present as exercise intolerance with prominent exertional dyspnea, progressive muscle weakness, spasticity, and neuropathy, but without cognitive impairment or cardiac involvement, or as global developmental delay, growth retardation, hypotonia, and spasticity. Hypertrophic cardiomyopathy, optic atrophy, seizures, and dysmorphic facial features have also been reported in the more severe phenotype. Serum lactate may be elevated, and muscle biopsy shows myopathic features and variably decreased activity of mitochondrial respiratory chain complexes.


Combined oxidative phosphorylation defect type 27

A rare mitochondrial oxidative phosphorylation disorder characterized by a variable clinical phenotype including infantile onset of epileptic encephalopathy, hypotonia, global developmental delay, failure to thrive, complex movement disorder, and liver involvement, as well as childhood onset of severe myoclonus epilepsy, cognitive decline, progressive hearing and visual impairment, and progressive tetraparesis. Serum lactate may be increased, and brain imaging shows variable atrophy and white matter abnormalities.


Combined oxidative phosphorylation defect type 29

A rare mitochondrial oxidative phosphorylation disorder characterized by microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction, and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.


Combined oxidative phosphorylation defect type 30

A rare mitochondrial oxidative phosphorylation disorder characterized by neonatal onset of hypotonia, feeding difficulties, deafness, and early fatal respiratory failure. Cardiac and liver involvement has been reported. Serum lactate is increased, and metabolic studies show decreased activity of mitochondrial respiratory complexes I and IV in skeletal muscle.


Combined oxidative phosphorylation defect type 39

A rare mitochondrial oxidative phosphorylation disorder characterized by early onset of severe developmental delay (sometimes with regression of developmental milestones) and intellectual disability, poor or absent speech, and hypotonia. Other features include movement disorder, seizures, or microcephaly, among others. Brain imaging may show features of Leigh syndrome with signal abnormalities in the basal ganglia or mid brain, cerebellar atrophy, or thin corpus callosum.


Combined oxidative phosphorylation defect type 4 is a rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by a neonatal onset of severe metabolic acidosis and respiratory distress, persistent lactic acidosis with episodes of metabolic crises, developmental regression, microcephaly, abnormal gaze fixation and pursuit, axial hypotonia with limb spasticity and reduced spontaneous movements. Neuroimaging studies reveal polymicrogyria, white matter abnormalities and multiple cystic brain lesions, including basal ganglia, and cerebral atrophy. Decreased activity of complex I and IV have been determined in muscle biopsy.


Combined oxidative phosphorylation defect type 7 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by a variable phenotype that includes onset in infancy or early childhood of failure to thrive and psychomotor regression (after initial normal development), as well as ocular manifestations (such as ptosis, nystagmus, optic atrophy, ophthalmoplegia and reduced vision). Additional manifestations include bulbar paresis with facial weakness, hypotonia, difficulty chewing, dysphagia, mild dysarthria, ataxia, global muscle atrophy, and areflexia. It has a relatively slow disease progression with patients often living into the third decade of life.


Combined oxidative phosphorylation defect type 8 is a mitochondrial disease due to a defect in mitochondrial protein synthesis resulting in deficiency of respiratory chain complexes I, III and IV in the cardiac and skeletal muscle and brain characterized by severe hypertrophic cardiomyopathy, pulmonary hypoplasia, generalized muscle weakness and neurological involvement.


Combined oxidative phosphorylation defect type 9 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V.


Combined pancreatic lipase-colipase deficiency is a disorder of lipid absorption and transport characterized by steatorrhea with foul-smelling stools from birth, diminished serum carotene and vitamin E and a combined deficiency of the pancreatic enzymes lipase and colipase. Patients are otherwise healthy and develop normally with no apparent pancreatic disease. There have been no further descriptions in the literature since 1990.


Combined pituitary hormone deficiencies, genetic forms

Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies. Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy.


Combined pulmonary fibrosis-emphysema syndrome

A rare interstitial lung disease characterized by the coexistence of emphysema and usual interstitial pneumonia, typically occurring in male smokers. Emphysema is usually encountered in the upper lobes, preceding fibrosis of the lower lobes. Patients present with severe dyspnea and markedly reduced diffusion capacity on functional testing, while spirometric values are relatively preserved. The syndrome is frequently complicated by pulmonary hypertension and acute lung injury.


A rare otorhinolaryngological malformation characterized by a unilateral or bilateral fistula located at the corner of the mouth, where the vermillion border of the upper lip meets that of the lower lip. The lesion is lined by labial mucosa. It is potentially susceptible to infection.


Truncus arteriosus (TA) is a rare congenital cardiovascular anomaly characterized by a single arterial trunk arising from the heart by means of a single semilunar valve (i.e. truncal valve). Pulmonary arteries originate from the common arterial trunk distal to the coronary arteries and proximal to the first brachiocephalic branch of the aortic arch. TA typically overrides a large outlet ventricular septal defect (VSD). The intracardiac anatomy usually displays situs solitus and atrioventricular (AV) concordance.

Summary:
Epidemiology
Prevalence ranges from 0.03 to 0.056 per 1,000 live births. In Europe, the average recorded prevalence is 1/10,000 births (including livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis). No striking difference in frequency is observed between the sexes, although most series contain more males than females.
Clinical description
Neonates with TA present with clinical features of congestive heart failure depending on the extent of the increase in volume of pulmonary blood flow and the presence or absence of truncal valve insufficiency. Symptoms of failure manifest as falls in pulmonary resistance and increases in pulmonary overcirculation occur. Tachypnea, tachycardia, excessive sweating, poor feeding may be the first signs to appear.
Etiology
The etiology of TA remains unknown. In experimental animal models, TA has been linked to abnormal development of cells from the neural crest that are normally located in the outflow region of the developing heart; this is also thought to be an important etiologic factor in some cases of human TA.
Antenatal diagnosis
Prenatal detection of truncus arteriosus by ultrasound is documented.
Management and treatment
In the last 10 to 15 years there have been clinically significant improvements in treatment with early repair. It is now recommended that TA is repaired in the neonatal period and morbidity and mortality are as low as 5% in selected series. Currently, surgical management consists of complete repair with closure of the VSD.

                            Last update:
                            March 2005

                            - Expert reviewer(s):
                            Dr Luigi BALLERINI


A group of rare lymphatic malformation disorders characterized by solitary or multifocal, benign, congenital malformation of the lymphatic vessels in the soft tissues, resulting in painless cystic lesions, which are predominantly found in the head and neck (but may affect any site), and which have varying clinical presentation depending on specific size and location of lesion. Categorization into macrocystic lympathic malformations, microcystic lymphatic malformations or mixed cystic lymphatic malformations is reported based on the size of the cyst(s) contained within the lesion. Functional deficits and compromise of vital functions (including breathing, feeding) may be observed.


Common variable immunodeficiency (CVID) comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunizations and susceptibility to bacterial infections, predominantly caused by encapsulated bacteria.

Summary:
Epidemiology
Prevalence is estimated at 1/25,000 among Caucasians and CVID affects men and women equally.
Clinical description
While some patients are diagnosed with CVID in early childhood, the major peak of onset lies between the second and third decade of life, frequently with several years delay between onset and diagnosis. Over 98% of patients present with recurrent bronchitis, sinusitis, otitis and pneumonia, and chronic pulmonary damage is the major complication. About 25% of patients develop autoimmune phenomena; immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are the most common (see these terms). Lymphoproliferative disorders such as generalized lymphadenopathy and/or splenomegaly are present in up to 40% of patients, and there is an increased risk of developing gastrointestinal and lymphoid malignancies, especially non-Hodgkin's lymphoma (see this term). Up to 57% of patients develop bronchiectasis. Patients with TACI-deficiency are more likely to be affected by lymphoproliferation and autoimmunity. There is considerable variation in the clinical presentation in patients with a similar genotype.
Etiology
CVID can be due to an intrinsic B cell defect (for example CD19-deficiency caused by mutations in CD19; 16p11.2), an intrinsic T cell defect (for example ICOS-deficiency caused by mutations in ICOS; 2q33), mutations in TNF receptors (such as TACI-deficiency or BAFFR-deficiency caused by mutations in TNFRSF13B and TNFRSF13C respectively; 17p11.2 and 22q13.1-q13.31) or without a known genetic defect. Other monogenic defects reported include MSH5, CD81 and CD20 deficiencies.
Diagnostic methods
Diagnosis should be suspected in patients with recurrent sinopulmonary infections exceeding an age-specific frequency, and is based on exclusion of other causes of hypogammaglobulinemia. Analyses of lymphocyte function, including analysis of specific antibody responses after vaccination, and immunophenotyping of T and B cells strengthen the diagnosis and indicate subgroups of CVID. Ultrasound and CT of the abdomen may be necessary to assess additional complications including enlarged abdominal lymph nodes, spleen and liver pathology or granulomas.
Differential diagnosis
Differential diagnosis include other causes of hypogammaglobulinemia including loss of gammaglobulins via the intestine or urine, hematological malignancies, viral infections or drug-induced loss of B-cell function.
Genetic counseling
Most cases are sporadic but about 20% are thought to be familial with either autosomal dominant (80%) or autosomal recessive (20%) inheritance. TACI-deficiency is estimated to occur in approximately 10% of cases; the other defects are very rare.
Management and treatment
There is no curative therapy. Treatment is based on immunoglobulin replacement therapy, using pooled human immunoglobulin, usually administered intravenously or subcutaneously. To reduce long-term pulmonary sequelae, targeted antibiotic treatment is necessary. Patients with bronchiectasis may benefit from lung physiotherapy. The frequently occurring cytopenias require monitoring, and specific treatment such as splenectomy may be indicated. Concurrent autoimmune disorders or malignant disease require specific treatment.
Prognosis
Patients with bacterial infections only have a better prognosis than patients with additional complications and can have nearly normal life expectancy, especially if diagnosis and treatment occurs soon after the onset of symptoms.

                            Last update:
                            June 2010

                            - Expert reviewer(s):
                            Dr Karin ENGELHARDT  - Pr Bodo GRIMBACHER  -  P HERHOLZ


Complement component 3 deficiency is a rare, genetic, primary immunodeficiency characterized by susceptibility to infection (mainly by gram negative bacteria) due to extremely low C3 plasma levels. Patients typically present recurrent episodes of sinusitis, tonsillitis, and/or otitis, as well as upper and lower respiratory tract infections (including pneumonia) and skin infections, such as erythema multiforme. Autoimmune disease resembling systemic lupus erythematosus and mesangiocapillary or membranoproliferative glomerulonephritis may develop, resulting in renal failure.


Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome

A rare genetic disease characterized by CD55 deficiency with complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy with abdominal pain, diarrhea, vomiting, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption, leading to anemia and growth delay. Bowel inflammation and recurrent infections associated with hypogammaglobulinemia may also be observed.


Complete androgen insensitivity syndrome (CAIS) is a form of androgen insensitivity syndrome (AIS; see this term), a disorder of sex development (DSD), characterized by the presence of female external genitalia in a 46,XY individual with normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens.

Summary:
Epidemiology
The estimated incidence is between 1/20,000 and 1/99,000 live male births.
Clinical description
The typical presentation is primary amenorrhea in an adolescent female. CAIS may also present in infancy or childhood with an inguinal hernia or labial swelling containing a testis. Breast development at puberty is normal, but pubic and axillary hair is absent or scanty. The external genitalia are normal female but internal female genitalia are absent. Adult patients are tall. Other presentations may be serendipitous from a mismatch in prenatal sexing (XY) and birth female phenotype, history of an inguinal hernia repair in an older sister, or development of a pelvic tumor in later adult life.
Etiology
The condition is due to mutations in the androgen receptor (AR) gene which is located on the long arm of the X-chromosome (Xq11-12). The AR is a nuclear transcription factor comprising three functional domains. Mutations are distributed throughout the gene, predominantly in 5 of the 8 exons that code for the ligand binding domain. The CAIS phenotype is associated with an AR mutation that completely disrupts AR function; target cells do not respond to testosterone or dihydrostosterone (DHT). An AR mutation is found in more than 95% of patients with CAIS; 30% are de novo mutations.
Diagnostic methods
The diagnosis is based on clinical and biochemical findings in a female with a 46,XY karyotype. The typical hormone profile is increased basal luteinizing hormone (LH) and testosterone levels in adults, and increased testosterone levels in infants following human chorionic gonadotropin (hCG) stimulation. Serum anti-Müllerian hormone (AMH) levels are normal or increased. Pelvic ultrasound or MRI reveal absent Müllerian structures (uterus, Fallopian tubes and upper vagina), due to the action of testicular anti-Müllerian hormone (AMH). Wolffian duct derivatives (vas deferens, epididymis, seminal vesicle) are absent due to androgen resistance. Mutation analysis of the AR gene confirms the diagnosis.
Differential diagnosis
Differential diagnoses include 17-beta-hydroxysteroid dehydrogenase deficiency, Leydig cell hypoplasia, XY complete gonadal dysgenesis (Swyer syndrome), 5-alpha-reductase type 2 deficiency and variants of congenital adrenal hyperplasia (see these terms).
Antenatal diagnosis
Antenatal diagnosis is seldom indicated.
Genetic counseling
he condition is X-linked recessive. Affected families should be offered genetic counseling in order to be informed of the risk of recurrence and to identify other potential carriers in the family.
Management and treatment
Management includes removal of the testes, either after puberty when feminization is complete or before puberty, followed by estrogen replacement therapy at the age of puberty. Vaginal dilatation may be indicated to avoid dyspareunia. Adults require bone mineral density scans every five years. Psychological support is required for disclosure.
Prognosis
Prognosis for patients with CAIS is favorable if support and counseling are appropriate. Adults have normal female gender identity. Patients are infertile and have an increased risk of osteoporosis if hormone replacement is inadequate. The risk of carcinoma in situ (a pre-malignant disorder) and gonadoblastoma is less than 5%.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Ieuan HUGHES


A rare, congenital cardiac anomaly characterized by a common atrioventricular junction with a common AV valve, an interatrial communication just above the common AV valve (ostium primum defect), a posterior interventricular communication (inlet VSD), that results in shunting at both the atrial and ventricular level. Morphologically, the common atrioventricular valve has 4 or 5 leaflets including superior and inferior bridging leaflets with a single annulus.

Summary:
Epidemiology
Prevalence at birth of complete atrioventricular septal defect (CAVSD) is suggested to be 1/5,000 in Europe. Both sexes are equally affected.
Clinical description
Infants typically present within the first year of life with symptoms of congestive heart failure which may include feeding difficulties, excessive sweating, tachycardia, tachypnea, mild wheezing, failure to thrive, and poor peripheral blood perfusion. If untreated, affected individuals develop irreversible pulmonary hypertension which improves signs of congestive heart failure but worsens tolerance to effort and results in cyanosis and Eisenmenger syndrome. Recurrent pulmonary infections are common. Morphologically, the ventricles may be equal or nearly equal in size (balanced) or one of the ventricles may be significantly larger than the other (unbalanced). The balanced form is typically observed in Down syndrome. Unbalanced ventricles are associated with varying degrees of malalignment of the common atrioventricular valve over the hypoplastic ventricle and hypoplasia of the arterial valve above. Tetralogy of Fallot (TOF) is observed in 5-10% of CAVSD.
Etiology
CAVSD is strongly associated with Down syndrome and heterotaxy. Cilia gene mutations could be involved in isolated AVSD. A small fraction of CAVSD cases have been associated with NR2F2 (15q26.2), GATA4 (8p23.1), GATA6 (18q11.2) and CRELD1 (3p25.3) mutations.
Diagnostic methods
Echocardiography is used for postnatal diagnosis. Typical findings include a left and superior QRS axis in the frontal plane and counterclockwise depolarization. Chest X-ray may show ventricular enlargement and a greater anterior position of the left atrioventricular valve due to the inlet septal defect, which gives a ''goose neck'' appearance to le left ventricular outflow tract.
Differential diagnosis
Differential diagnosis includes other congenital cardiac anomalies that result in early heart failure including partial atrioventricular canal, atrial septal defects and large ventricular septal defects.
Antenatal diagnosis
CAVSD can be detected with fetal echocardiography; the detection rate is approximately 67%.
Genetic counseling
Atrioventricular septal defects (AVSD) can occur in the offspring of mothers with CAVSD.
Management and treatment
Digoxin, diuretics and angiotensin-converting enzymes may be used to treat congestive heart failure prior to surgery. Surgical repair is advised at 3 months of age and is typically performed between 3 and 6 months of age. The three classical techniques are single patch technique, two patch technique (most frequent), and the modified single patch technique. To avoid surgically induced AV block, the position of the AV node and bundle of His must be considered, with the AV node positioned more posteriorly and inferiorly, the non-branching bundle running slightly on the left side of the septal crest with the branching bundle being exposed. Pulmonary artery banding can be proposed before 3 months in very ill patients despite optimal medical therapy. Combined repair of other cardiac anomalies is often performed with desirable results. In case of associated tetralogy of Fallot, complete repair is usually delayed up until 1 year of age. Lifelong follow-up every 2 to 3 years is recommended.
Prognosis
Without surgery, many of the affected individuals will die in infancy. Prognosis after surgical repair is good; however, patients who weigh less the 3 kg or are less than 2.5 years old have a higher risk of mortality during surgery. Pregnancy increases the risk of developing left AVV regurgitation, arrhythmias, deterioration of heart failure, and is not recommended for women with severe pulmonary hypertension.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


A form of hydatiform mole characterized by abnormal hyperplastic trophoblasts and hydropic villi due to fertilization of an enucleated ovocyte by one or two haploid spermatozoa that can manifest with vaginal bleeding accompanied by nausea and frequent vomiting, hyperemesis gravidarum, risk of spontaneous miscarriage, hyperthyroidism, and has the potential of developing into choriocarcinoma.


Complete septate uterus is a rare, non-syndromic uterovaginal malformation characterized by a uterus that has a longitudinal septum which elongates from the uterine fundus to the internal or external cervical os. Most often women are asymptomatic, however dysmenorrhea, unilateral obstruction, and endometriosis could be observed. Unlike urinary tract abnormalities, which are very rarely associated, poor reproductive outcome is frequent.


A group of rare chromosomal anomalies characterized by constitutional structural chromosomal rearrangements, including translocations, invertions, duplications and deletions, involving at least three breakpoints on two or more chromosomes. Individuals with such arrangements may display various phenotypes including cognitive impairment, congenital abnormalities and infertility, while some can also be phenotypically normal. Both de novo and familial forms are reported.


A rare, genetic, primary bone dysplasia with decreased bone density characterized by fetal lethality, severe hypomineralization of the entire skeleton, barrel shaped thorax with short ribs, multiple intrauterine fractures of ribs and long bones, ascites, pleural effusion, and ventriculomegaly. Variable congenital developmental anomalies affecting the brain, lungs, and kidneys have also been associated.


Complex regional pain syndrome type 1 (CRPS1) is a form of complex regional pain syndrome (see this term) in which the pain is disproportionate to any known inciting event and is characterized by continuous pain, allodynia, or hyperalgesia as well as edema, coloration (changes in skin blood flow), or abnormal sudomotor activity in the region of pain. Onset of CRPS1 symptoms may occur within a few days to a month after an injury or trauma to the affected limb.


Complex regional pain syndrome type 2 (CRPS2), or causalgia is a form of complex regional pain syndrome that develops after damage to a peripheral nerve and is characterized by spontaneous pain, allodynia and hyperalgesia , not necessarily limited to the territory of the injured nerve, as well as at some point, edema, changes in skin blood flow or sudomotor dysfunction in the pain area.


Complex regional pain syndrome (CRPS) is a rare neurologic disease painful progressive condition that corresponds to a group of disorders characterized by a disproportionate spontaneous or stimulus-induced pain, accompanied by a variably mixed myriad of autonomic and motor disorders including symptoms such as swelling, allodynia, skin blood supply and trophic disturbances. CRPS most often affects one of the arms, legs, hands, or feet and usually occurs after an injury or trauma to that limb.


A rare vascular tumor characterized by a poorly circumscribed, infiltrative nodular lesion with vascular differentiation, centered in the dermis and subcutis. The tumor is composed of histologically benign, intermediate, and malignant components. Typical is an admixture of different components which include epithelioid and retiform hemangioendothelioma, spindle cell hemangioma, angiosarcoma-like areas, and benign vascular lesions. Predilection sites are the distal extremities. Many patients have a history of lymphedema. Local recurrence is frequent, while metastasis is rare.


A rare lymphoma characterized by the concurrent occurrence of two or more histologic types of lymphoma involving the same anatomic site. Composite lymphomas can be combinations of two non-Hodgkin lymphomas or of a non-Hodgkin and a Hodgkin lymphoma. In many cases, the tumors are clonally related. Clinical presentation and treatment are determined by the more aggressive component.


Conductive deafness-malformed external ear syndrome

A very rare, syndromic genetic deafness characterized by mild to moderate conductive hearing loss, dysmorphic pinnae and lip pits or dimples. The pinnae are usually small, cup-shaped, with helix folded forward, and hearing loss is associated with malformed ossicles and displacement of the external auditory canal.


Conductive deafness-ptosis-skeletal anomalies syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by conductive hearing loss due to atresia of the external auditory canal and the middle ear complicated by chronic infection, ptosis and skeletal anomalies (internal rotation of hips, dislocation of the radial heads and fifth finger clinodactyly). In addition, a thin, pinched nose, delayed hair growth and dysplastic teeth are associated. There have been no further descriptions in the literature since 1978.


Cone dystrophy with supernormal rod response (CDSRR) is an inherited retinopathy, with an onset in the first or second decade of life, characterized by poor visual acuity (due to central scotoma), photophobia, severe dyschromatopsia, and occasionally, nystagmus. Night blindness usually develops later in the course of the disease, but it can also be apparent from childhood. A hallmark of CDSRR is the decreased and delayed dark-adapted response to dim flashes in electroretinographic recordings, which contrasts with the supernormal b-wave response at the highest levels of stimulation.