A rare inborn error of tyrosine metabolism characterized by hypertyrosinemia with oculocutaneous manifestations and, in some cases, intellectual deficit.

Summary:
Epidemiology
Prevalence is unknown but less than 150 cases have been reported in the literature so far. The disease appears to be more common in Arab and Mediterranean populations.
Clinical description
Skin lesions occur in 80% of cases, ocular involvement in 75% of cases and neurologic findings and some degree of intellectual deficit in up to 60% of cases. Onset is variable but the ocular symptoms (redness, photophobia, excessive tearing and pain) usually develop in the first year of life. Ocular signs include corneal clouding with bilateral dendritiform corneal lesions (pseudodendritic keratitis), neovascularization, corneal ulceration and scarring, which may lead to decreased visual acuity. Cutaneous manifestations usually begin after the first year of life but may develop at the same time as the ocular symptoms. The skin lesions consist of nonpruritic, hyperkeratotic papules and plaques principally located on the palms and soles (palmoplantar hyperkeratosis). These lesions are painful and progressive and are often associated with hyperhidrosis. Central nervous system (CNS) involvement is highly variable with intellectual deficit (ranging from mild to severe) being the most common manifestation. Other signs of CNS involvement include behavioral problems, nystagmus, tremor, ataxia, and convulsions.
Etiology
Tyrosinemia type 2 is caused by mutations in the TAT gene (16q22.2) encoding tyrosine aminotransferase (TAT). The elevated levels of tyrosine caused by TAT deficiency appear to result in deposition of tyrosine crystals leading to an inflammatory response and the oculocutaneous findings. Tyrosine crystals were not found in skin lesions; it was suggested that intracellular tyrosine excess interfere with microtubules and tonofilaments. It has also been suggested that there is a correlation between the extent of the CNS involvement and the levels of tyrosine in the plasma.
Diagnostic methods
Diagnosis is established on the basis of the clinical findings and detection of high levels of plasma and urinary tyrosine, and elevated levels of urinary tyrosine metabolites (such as 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate and N-acetyltyrosine). The confirmation of the diagnosis is done by mutations analysis; TAT assays on liver biopsy samples are usually not necessary. Some patients with tyrosinemia type 2 may be identified through neonatal screening program studies.
Differential diagnosis
As the ocular findings are often the initial manifestations of the disease, the pseudodendritic keratitis is often mistaken for herpes simplex keratitis. Mutilating palmoplantar keratoderma with periorificial keratotic plaques is also part of the differential diagnosis.
Antenatal diagnosis
Antenatal diagnosis is possible with chorionic villus sampling and amnioncentesis when a mutation has been identified in the family.
Genetic counseling
Tyrosinemia type 2 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.
Management and treatment
Management revolves around dietary restriction of phenylalanine and tyrosine. Oral retinoids may also be administered for treatment of the skin lesions.
Prognosis
The controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. However, the extent to which this controlled diet prevents the CNS involvement is unclear.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr Corinne DE LAET | MetabERN*

                                * European Reference Network


A rare inborn error of tyrosine metabolism characterized by mild hypertyrosinemia and increased urinary excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate.

Summary:
Epidemiology
It is the least frequent form of tyrosinemia with less than 20 cases reported in the literature so far.
Clinical description
The clinical picture is highly variable ranging from asymptomatic in some patients identified through neonatal screening program studies to patients with neurologic manifestations including intellectual deficit, ataxia, tremors and seizures.
Etiology
Tyrosinemia type 3 is caused by mutations in the HPD gene (12q24.31) encoding 4-hydroxyphenylpyruvate dioxygenase.
Diagnostic methods
Detection of elevated tyrosine in the blood and detection of tyrosine derivatives in the urine is suggestive of the disease. The diagnosis is confirmed by enzyme assay, revealing accumulation of 4-hydroxyphenylpyruvate dioxygenase in the liver or kidney, or by mutation testing.
Differential diagnosis
The differential diagnosis broadly includes neurological disorders with psychomotor and/or intellectual disability of other etiology.
Antenatal diagnosis
Antenatal diagnosis is possible when a disease-causing mutation has been identified in the family.
Genetic counseling
Tyrosinemia type 3 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.
Management and treatment
Although it has not been clearly established that treatment prevents the onset of symptoms, it is currently recommended that, patients with tyrosinemia type 3 follow a phenylalanine- and tyrosine-restricted diet.
Prognosis
Tyrosinemia type 3 has no impact on life expectancy. Intellectual disability, usually mild to moderate, may require adaptations to daily life.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr Corinne DE LAET | MetabERN*

                                * European Reference Network


Uhl anomaly is characterized by an almost complete absence of the myocardium in the right ventricle resulting in a thin walled nonfunctional right ventricle manifesting with cardiac arrhythmias and right ventricular failure. Cases of partial absence of right ventricular myocardium which remains asymptomatic or mildly symptomatic until adulthood have also been reported. Patients presenting with complete Uhl anomaly should be considered for cardiac transplantation.


Ulbright-Hodes syndrome is characterised by renal dysplasia, growth retardation, phocomelia or mesomelia, radiohumeral fusion, rib abnormalities, anomalies of the external genitalia and a potter-like facies. The syndrome has been described in three infants (one pair of sibs and an unrelated case), all of whom died shortly after birth from respiratory distress resulting from pulmonary hypoplasia and oligohydramnios caused by renal dysplasia. The mode of transmission appears to be autosomal recessive.


Ulerythema ophryogenesis is characterised by inflammatory keratotic papules occurring on the face, which may be followed by scars, atrophy and alopecia. Prevalence is unknown but the disease, affecting mainly children and young adults, is rare. Erythema with mild hyperkeratosis of the hair follicles resulting in rough papules is observed on the cheeks and lateral aspects of the eyebrows. The disorder occasionally extends to the adjacent scalp, ears and forehead and rarely to the extensor surfaces of the limbs. Symptoms regress with age, although loss of the lateral aspects of the eyebrows can occur. Many cases occur sporadically; autosomal dominant inheritance has also been reported. There is no particular treatment, but patients should avoid sun exposure without UV protection.


A form of congenital muscular dystrophy characterized by congenital weakness, hypotonia, proximal joint contractures, marked hyperlaxity of the distal joints, with a loss of ambulation (if achieved) and uniform respiratory insufficiency during childhood.

Summary:
Epidemiology
A Northern England study of genetic muscle disease reported an estimated prevalence of Ullrich congenital muscular dystrophy (UCMD) of 1/769,231.
Clinical description
The first signs noted are typically noted in utero with decreased fetal movement. Characteristic features at birth include hypotonia, torticollis, contractures of the proximal joints, hyperlaxity of the distal joints, kyphoscoliosis, abnormal positioning of the hands (wrist flexion) and feet (ankle dorsiflexion), hip dislocation, and prominent calcanei. Independent walking is not always achieved, and progression of muscle weakness and joint contractures result in loss of ambulation by 10-11 years old. Progressive, severe respiratory insufficiency occurs in all affected individuals by ~11 years old. Congenital kyphoscoliosis may occur. Spinal rigidity with concomitant scoliosis typically manifest at ~7 years, with scoliosis surgical repair performed at ~11 years. Skin manifestations include keratosis pilaris/follicular keratosis, prominently along the extensor surfaces of the arms and legs, keloid scars, and atrophic scars.
Etiology
UCMD is caused by heterozygous or biallelic pathogenic variants (PVs) in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3).
Diagnostic methods
The diagnosis is based on clinical signs, muscle imaging (MRI helps to identify characteristic patterns of abnormal muscle signaling), biopsy (revealing degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue), and muscle immunohistochemical features (ranging from absent collagen VI to mislocalized collagen VI) and the identification of a PV or PVs by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome, kyphoscoliotic Ehlers-Danlos syndrome, classic Ehlers-Danlos syndrome, Marfan syndrome, congenital contractural arachnodactyly, TTN-related myopathy, RYR1-related myopathy, SELENON-related myopathy, other forms of congenital muscular dystrophy, and spinal muscular atrophy.
Antenatal diagnosis
Once PV have been identified in an affected family member, prenatal diagnosis for a pregnancy and preimplantation genetic testing are possible.
Genetic counseling
UCMD is typically caused by a de novo autosomal dominant PV in COL6A1, COL6A2 or COL6A3, in which case, each child of an affected individual has a 50% chance of inheriting the PV. Less commonly, UCMD is inherited in an autosomal recessive manner; if both parents are carriers of a disease-causing mutation, they should be informed that there is a 25% risk of having an affected child with each pregnancy. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in COL6-RDs and should be considered, given the implications for recurrence risk assessment.
Management and treatment
Currently, there is no curative treatment. Careful pulmonary surveillance and proactive care dramatically improve the quality of life of affected individuals, however. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) is necessary by ~11 years. Use of a mechanical insufflator-exsufflator promotes airway clearance. Without adequate respiratory support with NIV, respiratory failure leads to early death in adolescence. Surveillance of the spine and surgical correction of scoliosis, if indicated, should be provided. Physical and occupational therapy are important for providing recommendations for joint stretching, swimming, and aquatherapy. Achilles tendon contractures should be managed with splints and/or tendon release surgery. Feeding and nutrition support should be provided for failure to thrive.
Prognosis
UCMD is a severe progressive disorder. Progressive respiratory insufficiency uniformly necessitates the initiation of nocturnal non-invasive ventilation by ~11 years of age. Most patients either are unable to walk or can walk for a period of time, with full-time wheelchair dependence by ~10-11 years of age.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr Carsten G. BONNEMANN  - Dr A. Reghan FOLEY


Ulna hypoplasia-intellectual disability syndrome

Ulna hypoplasia - intellectual deficit is a very rare syndrome characterized by mesomelic shortness of the forearms, bilateral clubfeet, aplasia or hypoplasia of all nails and severe psychomotor retardation.

Summary:
Epidemiology
It has been reported in two sibs.
Genetic counseling
The family is suggestive of autosomal recessive inheritance.
Prognosis
Prognosis is poor.

                            Last update:
                            September 2010


Ulnar hypoplasia-split foot syndrome is characterised by the association of severe ulnar hypoplasia, absence of fingers two to five, and split-foot. It has been described in four males belonging to two generations of the same family. X-linked recessive inheritance is suggested, but autosomal dominant transmission cannot be excluded.


A rare congenital anomalies syndrome characterized by a variable spectrum of ulnar defects, mammary and apocrine gland hypoplasia and genital anomalies. The most frequent signs include fifth finger and dental anomalies, delayed puberty and mammary hypoplasia. Short stature and obesity are common.

Summary:
Epidemiology
Up to date, approximately 128 cases of Ulnar-mammary syndrome (UMS) have been reported in the literature.
Clinical description
Upper limb defects are the most common presenting feature of UMS at birth. Whilst the upper limbs can be normal, the limb phenotype is variable and can range from hypoplasia of the distal phalanges of the fifth finger(s), camptodactyly and/or postaxial polydactyly to absent ulnar ray digits, absent or hypoplastic ulna and a reduced humerus at the severe end of the spectrum. Abnormalities may be bilateral but are frequently asymmetric; lower limb defects have not been reported. The variable mammary and apocrine features of UMS may not be apparent until puberty and include mammary gland tissue hypoplasia (leading to absence of breast development and the inability to lactate), areolar or nipple hypoplasia, inverted nipples and apocrine gland hypoplasia (that can result in diminished perspiration and body odor). Absent or reduced axillary hair has also been described. Shared facial features of UMS include a wide face tapering to a prominent chin, a broad nasal tip, a wide nasal base, and a bifid tongue tip. Genital defects can include micropenis, shawl scrotum, cryptorchidism, septate uterus, and imperforate hymen. Delayed puberty is noted, particularly in males (79%), due to hypogonadism. Obesity and short stature are also common in individuals with UMS and a pituitary endocrine deficiency (growth hormone, pituitary hypoplasia) has been suggested as a possible cause. Abnormalities of the teeth with ectopic, hypoplastic or absent canines have been noted in a number of individuals. Cardiac defects (ventricular septal defects or conduction abnormalities), renal and anal anomalies (imperforation, anteposition) have been reported in a few cases.
Etiology
UMS is caused by loss-of-function variants in the TBX3 gene (12q24.21). A hotspot of missense variants is observed in the DNA-binding domain of the TBX3 protein. TBX3 is a member of the T-box gene family. These genes encode transcription factors that have been shown to be important in embryologic development and in the morphogenesis of multiple organ systems.
Diagnostic methods
Diagnosis of UMS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses of TBX3.
Differential diagnosis
Differential diagnoses include limb-mammary syndrome (due to TP63 variants) and Poland syndrome (which is sporadic).
Antenatal diagnosis
Prenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Ulnar Mammary syndrome mutation.
Genetic counseling
UMS is an autosomal dominant condition commonly reported in families. There is an important inter- and intra-familial variability in expression; however, there is no obvious phenotypic difference between those who have missense variants and those who have frameshift or stop-gain variants. Genetic counseling is possible for affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, endocrinologists, cardiologists, as well as social support networks.
Prognosis
Prognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies and of endocrinologic anomalies (short stature, infertility, etc.). Life expectancy is the same as in the general population.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Perrine BRUNELLE | ITHACA*

                                * European Reference Network


Ulnar/fibula ray defect-brachydactyly syndrome

A rare congenital malformation syndrome characterized by ulnar hypoplasia associated with hypoplastic to absent fourth and/or fifth digits, fibular hypoplasia, short stature and facial dysmorphism.


A rare syndromic intestinal malformation characterized by ulcer formation in the umbilical cord associated with congenital upper-intestinal atresia, typically presenting with intra-uterine hemorrhaging from the ulcer site and subsequent fetal bradycardia.

Summary:
Epidemiology
Whilst about 66 cases have been described to date in the medical and scientific literature, the entity is probably grossly under-reported due to lack of awareness.
Clinical description
Umbilical cord ulceration (UCU) occurs in the context of duodenal or jejunal intestinal atresia, developing in 6.5-13.6% of infants with a prenatal diagnosis of congenital upper intestinal atresia (CUIA). Onset of the UCU typically occurs from gestational week 30 onwards. Symptoms of UCU usually begin with the onset of premature labor or rupture of membranes, where the increased intra-uterine pressure causes rupture of the umbilical vessel into the amniotic cavity, triggering massive fetal hemorrhage and subsequent bradycardia. Severe anemia is typically present at birth. The degree of ulceration ranges from only desquamation of the epithelium to exposure of the umbilical artery or vein. Cases that do not significantly hemorrhage, especially lower grade lesions, may go undiagnosed.
Etiology
Whilst the exact mechanism of pathogenesis is unclear, it is suspected that UCU is closely related to in-utero regurgitation of bile. Other mechanisms proposed include vascular hyper-reactivity and secondary ischemia, causing simultaneous occurrence of both UCU and CUIA, due to an epithelial abnormality (similar to the association of epidermolysis bullosa with intestinal atresia).
Diagnostic methods
Prenatal ultrasound findings of CUIA with polyhydramnios should raise suspicion of associated UCU. However, in these cases, confirmation of diagnosis is most often done postnatally upon examination of umbilical cord.
Differential diagnosis
Differential diagnoses include absence of Wharton's jelly, omphalomesenteric duct with gastric mucosa, umbilical cord hemangioma, and umbilical hematoma.
Antenatal diagnosis
Suggestive ultrasound (US) findings include signs of CUIA and polyhydramnios. Whilst there is an increased risk of UCU in cases of CUIA, prenatal detection of UCU is challenging. In high-risk cases, increased frequency of ultrasound monitoring with a meticulous evaluation of the umbilical cord, especially at the fetal end, is advisable but technically difficult. Findings suspicious of blood in amniotic fluid include observations of bleeding from the umbilical cord by color Doppler or changes in the luminosity of the amniotic fluid indicating the presence of blood. Measurement of bile acid concentration in amniotic fluid can further help in segregation of high-risk cases.
Management and treatment
It is currently difficult to present a method by which sudden fetal death can be prevented. The risk of UCU must be explained elaborately to the parents of fetuses with CUIA. Daily monitoring of high risk cases with fetal kick chart and non‐stress test (NST) is advisable for early detection of UCU. Termination of pregnancy may be considered when hemorrhage is confirmed via amniocentesis or ultrasound findings are suggestive of blood in amniotic fluid. In cases of polyhydramnios with CUIA, continuous fetal heart monitoring at the onset of premature labor or premature rupture of membranes has been found to improve outcome. Awareness of this association and immediate delivery of fetus at first signs of hemorrhage or hypoxia will help prevent stillbirths and poor neonatal outcomes.
Prognosis
Prognosis of Umbilical cord ulceration-intestinal atresia syndrome is poor, with intra-uterine fetal or neonatal death occurring in the majority of cases. Prompt intervention, initiated with immediate delivery at the first signs of fetal hemorrhage/hypoxia, may improve the outcome.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Sangeeta GUPTA


UMOD-related autosomal dominant tubulointerstitial kidney disease

A form of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to UMOD mutations that is clinically characterized by bland urinalysis (absence of blood or protein in the urine), chronic kidney disease (CKD) leading to end-stage kidney disease (ESKD) between 20 and 80 years, and gout occurring in 50% of affected individuals.

Summary:
Epidemiology
Whilst prevalence data is limited, it is estimated at approximately 1/600,000 in Austria and 1/110,000 in the UK. The disease has equal prevalence among all studied racial groups.
Clinical description
CKD is usually first evident in the early twenties, though many children will have some evidence of mildly decreased kidney function by 18 years. Ten percent of affected individuals develop gout before age 18 years. Many individuals are first recognized with gout or CKD in their twenties. Patients will have slowly progressive loss of kidney function. The mean age of ESKD is approximately 49 years of age, though the age varies widely from 20 to over 70 years, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear. Gout will develop in approximately 50% of affected individuals over time, often preceding significant loss of kidney function.
Etiology
The disorder is caused by mutations in the UMOD gene, resulting in a mutated uromodulin protein that deposits within the endoplasmic reticulum, leading to cell stress, accelerated apoptosis, and progressive chronic kidney disease.
Diagnostic methods
Diagnosis is suspected in individuals who have chronic kidney disease, a bland urinary sediment, and a family history of kidney disease. Gout presenting in adolescence or in a young woman is suggestive for ADTKD-UMOD. Mutational analysis is the preferred means of diagnosis, either by direct sequencing if the family has a known UMOD mutation or by multi-gene panel or whole exome sequencing, both of which will identify alternative genetic causes.
Differential diagnosis
ADTKD-MUC1 is almost clinically indistinguishable from ADTKD-UMOD except that gout is less prevalent in ADTKD-MUC1 and only occurs after the development of CKD. ADTKD-REN due to mutations in the segment of the gene encoding mature renin is clinically identical to ADTKD-UMOD, with early gout, CKD, and autosomal dominant inheritance. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-UMOD may be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible if there is known mutation in the family.
Genetic counseling
The disorder is autosomal dominant. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing may be performed in children to prevent the risk of gout development with early treatment with allopurinol. If gout is not prevalent in the family, testing in childhood is not recommended. Relatives should be informed of their risk of ADTKD-UMOD, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.
Management and treatment
The only specific treatment for this disease is gout prevention with allopurinol or febuxostat. Gout is lifelong and worsens as CKD worsens, preventative therapy is thus important in patients who develop gout. Patients with ADTKD-UMOD are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial UMOD mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.
Prognosis
Whilst there is wide variation in onset of ESKD, many patients diagnosed today will not develop ESKD for more than two decades, with a current mean age of 49 years. Use of dialysis is variable, ranging from the third decade or as late as the eighth decade of life. Survival post-transplant is comparable to the general ESKD transplant population.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH


Unclassified myelodysplastic syndrome (MDS-U) is a subtype of myelodysplastic syndrome (MDS; see this term) with atypical features of uncertain clinical significance.

Summary:
Epidemiology
Prevalence is unknown but MDS-U appears to account for a very low proportion of MSD cases.
Clinical description
Unclassified MDS covers cases that cannot be allocated to another subtype of MSD after a full diagnostic work-up has been performed including clinical, morphologic, immunophenotypic, or cytogenetic testing. One or more cytopenias are a standard feature of MDS-U but other clinical features are variable. The following cases are considered to fall into this subtype: features of refractory cytopenia with uni- or multi-lineage dysplasia (RCUD, RCMD, see these terms) but with 1% blasts in peripheral blood, unilineage dysplasia with pancytopenia, and persistent cytopenias without morphological features of MDS associated with characteristic cytogenetic abnormalities.
Etiology
The etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.

                            Last update:
                            February 2015


A rare myelodysplastic/myeloproliferative neoplasm characterized by clinical, laboratory, and morphological features of both myelodysplastic syndrome and myeloproliferative neoplasm at onset, in the absence of recent cytotoxic or growth factor therapy, and without Philadelphia chromosome, BCR-ABL1 or PCM1-JAK2 fusion, or rearrangement of PDGFRA, PDGFRB, or FGFR1. Cases of a previously well-defined myeloproliferative neoplasm developing dysplastic features are excluded, and the criteria for any other myelodysplastic/myeloproliferative neoplasm, myelodysplastic syndrome, or myeloproliferative neoplasm are not met.


A rare vasculitis characterized by an inflammatory disease of blood vessels which cannot be assigned to any of the known categories of vasculitis. Clinical features are highly variable, depending on the nature and extent of the inflammatory process, as well as the type of vessels and organ systems involved.


Uncombable hair syndrome (UHS), or pili trianguli et canaliculi, is a rare scalp hair shaft dysplasia.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Onset is usually between ages 3 months and 12 years. Hair becomes progressively silvery-blond or straw-colored, dry and disordered, standing out from the scalp and growing in different directions, and being unmanageable to comb it flat. The quantity of hair stays normal. Microscopic analysis reveals a longitudinal groove of the hair shaft with a triangular or kidney-shaped section. The anomaly is clinically detectable when approximately 50% of hairs are affected. Several conditions have been reported to occur with UHS such as ectodermal dysplasia, retinal dysplasia, retinal pigmentary dystrophy, juvenile cataract, digit abnormalities, tooth enamel anomalies, oligodontia, phalango-epiphyseal dysplasia, alopecia areata, atopic eczema, and ichthyosis vulgaris.
Etiology
The stiffness and brightness of hair are supposed to result from a misshapen dermal papilla inducing an anomaly in the keratinization of the inner root sheath.
Diagnostic methods
Diagnosis relies on clinical and microscopic observation, but electron microscopic analysis of hair shaft can eliminate other hair anomalies.
Differential diagnosis
Differential diagnosis includes Rapp-Hodgkin ectodermal dysplasia, loose anagen hair syndrome, ectrodactyly, cleft/lip palate syndrome, familial tricho-odonto-onchyial ectodermal dysplasia with syndactyly and other ectodermal dysplasias.
Genetic counseling
UHS is likely to be an autosomal dominant inherited disease with a variable penetrance but no causal gene has been identified yet.
Management and treatment
UHS spontaneously regresses in late childhood and only gentle care including conditioners, soft brushes and avoidance of harsh treatments cares of the hair are recommended. Biotin treatment as been used in several patients and might be useful to control nail fragility, leading to acclaimed increase in hair growth after 4 months of supplementation.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Alexander NAVARINI


Underterminate colitis designates a rare inflammatory bowel disease that clinically resembles Crohns disease and ulcerative colitis (see these terms) but that cannot be diagnosed as one of them after examination of an intestinal resection specimen.


A rare, aggressive, malignant, epithelial carcinoma of the esophagus characterized, macroscopically, by an exophytic mass with central ulceration located on the esophagus and, histologically, by a sheet-like growth of neoplastic cells without significant glandular, squamous or neuroendocrine differentiation. Patients may present with progressive dysphagia, long-standing history of gastroesophageal reflux, weight loss, anemia, abdominal or chest pain/pressure, dyspnea, and/or hematemesis. Presence or history of Barrett esophagus is frequently associated.


Undifferentiated carcinoma of liver and intrahepatic biliary tract is an extremely rare epithelial tumor of the liver and biliary tract which presents heterogenous histological findings and not yet fully defined clinicopathological characterisitcs. Patients usually present with nonspecific signs and symptoms, such as abdominal pain, nausea, vomiting, anorexia, weight loss and/or jaundice. Invasive growth, high metastatic potential and a rapid clinical course are typically associated.


Undifferentiated carcinoma of stomach is a rare epithelial tumour of the stomach that lacks any features of differentiation beyond an epithelial phenotype. The presenting symptoms are usually vague and nonspecific, such as weight loss, anorexia, fatigue, epigastric pain and discomfort, heartburn and nausea, vomiting or hematemesis. Patients may also be asymptomatic. Ascites, jaundice, intestinal obstruction and peripheral lymphadenopathy indicate advanced stages and metastatic spread.


Undifferentiated carcinoma of the corpus uteri is a rare cancer of corpus uteri presenting as a large, polypoid, intraluminal mass with necrosis, composed of small to intermediate-size, relatively uniform, dyshesive cells displaying no differentiation. It usually presents with dysfunctional bleeding or vaginal discharge and, less often, abdominal pain. Association with Lynch syndrome was reported.


Undifferentiated carcinoma with osteoclast-like giant cells of pancreas

A rare type of pancreatic ductal adenocarcinoma characterized by composition of non-neoplastic osteoclast-like multinucleated giant cells, a mononuclear histiocytic component, and the neoplastic cells, which vary from spindle-shaped to epithelioid and can be very large and pleomorphic. Clinical features of pancreatic ductal adenocarcinoma include abdominal pain, nausea, weight loss, jaundice, and new-onset diabetes.


Undifferentiated connective tissue syndrome

A rare systemic autoimmune disease characterized by the presence of signs and symptoms suggestive of a systemic autoimmune disease that do not fulfil the existing classification criteria. The main clinical manifestations are arthritis with arthralgia, Raynaud's phenomenon, xerostomia, xerophthalmia, and leukopenia, while neurologic or renal involvement are virtually absent.


Undifferentiated embryonal sarcoma of the liver

Embryonal sarcoma of the liver is a rare primary malignant hepatic neoplasm of childhood of mesenchymal origin. It can rarely occur in adults. It is characterized by abdominal mass, right upper quadrant or epigastric pain, nausea, anorexia, intermittent fever or headache.


An aggressive sarcoma of soft tissues or bone that can arise from any part of the body, clinically presenting as swelling, mass, pain, pathological fracture and occasional systemic features and is characterized by high local recurrence and significant metastasis.

Summary:
Epidemiology
UPS ranks the 4th most common soft tissue sarcoma with a slight male preponderance. The incidence has been evaluated to be close to 0.8-1 new case per 100000 per year in one European series.
Clinical description
The tumor arises most commonly during the sixth and seventh decades of life. The most common sites of involvement include lower extremities (mainly thigh) followed by upper arms, retroperitoneum, viscera, head and neck (in childhood). Primary osseous UPS most commonly occurs in distal femur, proximal tibia, proximal femur and humerus. Patients may present pain, swelling / mass and pathological fractures. In the skin, UPS presents as a relatively painless, rapidly enlarging nodule. Anorexia, malaise, fever and weight loss are present in retroperitoneal and inflammatory forms of UPS. Most UPS recur locally; distant metastases are common (the most frequent is lung). Regional metastases are rare.
Etiology
UPS is thought to be derived from a primitive mesenchymal cell capable of differentiating into histiocytes, fibroblasts, myofibroblasts and osteoclasts. The etiology of the tumor remains unknown. Prior radiation therapy is a likely risk factor in some cases.
Diagnostic methods
Any tumor mass over 5 cm is suspected to be a sarcoma. Magnetic resonance imaging (MRI) is the imaging method of choice for limbs and shows a high signal on T2 weighted images. Histology of biopsy specimen prior to any treatment is crucial to reach diagnosis and shows pleomorphic spindle cell population with large atypical cells frequently exhibiting numerous irregular mitotic figures, associated regions of hemorrhage and necrosis, associated lymphohistiocytic infiltrate and invasion of dermis. Immunohistochemical staining is negative for S-100, HMB-45, CD34 and cytokeratin which assists in ruling out other soft tissue tumors. Most cases previously diagnosed as malignant fibrous histiocytoma have been reclassified into other histological types of sarcoma.
Differential diagnosis
When occurring in skin, UPS is difficult to differentiate from atypical fibroxanthoma or dermatofibrosarcoma protuberans (see this term). Histological differential diagnoses include leiomyosarcoma, rhabdomyosarcoma, lymphoma, and melanoma (see these terms).
Management and treatment
UPS should be referred to an expert/ reference center for primary biopsy, expert pathology review, and multidisciplinary treatment. Immediate surgery of a mass without knowledge of its histological nature is strongly discouraged because it is associated with an increased risk of death due to inappropriate resection and increased risk of relapse. UPS is best treated by wide surgical excision. Sometimes amputation may be necessary to remove the whole lesion. Adjuvant radiotherapy is given for high-grade, large (>5 cm), deep-seated tumors, in limb sparing surgeries and when negative margins are not obtained. For non-operable sarcomas, primary radiation therapy could be an option, but usually doxorubicin containing regimens are preferred options in first-line setting for locally irresectable and/or metastatic lesions. Chemotherapy (CHT) with ifosfamide, trabectedin, dacarbazine, pazopanib have demonstrated efficacy in UPS and are registered and available in most European Union countries.
Prognosis
A 5-year overall survival rate of 48% has been reported for patients with head and neck tumors versus 77% for patients with tumors arising on the trunk and extremities. The childhood variant appears have better prognosis.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Jean-Yves BLAY


Unexplained long-lasting fever/inflammatory syndrome

A rare systemic disease characterized by febrile illness (body temperature >38.3°C on several occasions) or inflammation (elevated serum C-reactive protein and erythrocyte sedimentation rate) lasting at least three weeks and for which no specific diagnosis is achieved despite extended diagnostics.


A rare lymphoid hemopathy characterized by involvement of a single lymph node or a group of lymph nodes in one lymph node station (most commonly in the mediastinum, neck, abdomen, or retroperitoneum). Histopathologically, it may occur as a hyaline vascular subtype with hyaline-vascular follicles and a fibrotic and hypervascular stroma with sinus compression, or a mixed/plasmacytic subtype with dense, interfollicular sheets of (usually polytypic) plasma cells extending to the cortex, and variably sized lymphoid follicles including some with regressive changes. Clinically, most patients are asymptomatic, and lesions are detected incidentally.


A rare non-syndromic uterine malformation characterized by a uterus with two uterine horns and only one cervix, resulting from a failure in the fusion of the two Müllerian structures. Depending on the degree of the fusion deficiency, the malformation may be complete with the cavities separated up to the internal orifice of the cervix and not linked, or partial when there is some linkage. Patients may present recurrent pregnancy loss or preterm labor.


Unilateral focal polymicrogyria (BFPP) is the mildest sub-type of polymicrogyria (PMG; see this term), a cerebral cortical malformation characterized by excessive cortical folding and abnormal cortical layering, that affects only one small region of the brain and that may show no neurologic involvement.


Unilateral multicystic dysplastic kidney

A rare form of multicystic dysplastic kidney (MCDK), a congenital anomaly of the kidney and urinary tract (CAKUT), in which one kidney is large, distended by multiple cysts, and non-functional.

Summary:
Epidemiology
Unilateral MCDK is the most common form of MCDK with a birth prevalence estimated at 1/4,300 live births.
Clinical description
Unilateral MCDK frequently presents antenatally at routine ultrasound scans, with the majority detected around the 20th week of gestation. The large majority of patients are asymptomatic but unilateral MCDK may occasionally present with abdominal obstructive signs (abdominal distention, feeding difficulties, respiratory distress) when the cysts become too large. Patients may also develop hypertension, proteinuria, and renal failure in the long run. The contralateral renal tract has an increased incidence of additional CAKUT such as vesicoureteral reflux and pelvi-ureteric junction obstruction (PUJO). Hypertrophy of the contralateral kidney may occur in 24-46% cases before birth, and in up to 80% in the years after birth.
Etiology
Unilateral MCDK results from disrupted nephrogenesis but the exact pathogenic mechanism is still unknown. Disturbed formation of nephrons could result from impaired fetal urine flow early in development. Mutations in the HNF1B gene (17q12), coding for hepatocyte nuclear transcription factor 1beta, associated with renal cysts and diabetes syndrome, have been detected in cases of unilateral MCDK. MCDK is also linked to gestational diabetes and to the use of some medications during pregnancy, such as anti-epileptic drugs.
Diagnostic methods
Diagnosis is mainly based on prenatal ultrasound showing large hypoechogenic non-communicating cysts within an irregularly outlined kidney with no visible renal pelvis. A tiny remnant kidney can be observed if the cysts have involuted. Complete prenatal involution has been described in 5% of MCDK, with complete involution in 50% during the first decade of life. Histologic examination shows that cysts are surrounded by undifferentiated and metaplastic cells with occasional residual functional renal tissue with recognizable glomeruli and proximal tubules. Renography with technetium-99m-labeled dimercaptosuccinic acid may show little or no renal uptake. As this has no clinical consequences, renography is not routinely indicated.
Differential diagnosis
Differential diagnoses include PUJO, in which the largely dilated calices may appear to be cysts, or in case of involuting MCKD, renal hypoplasia or renal agenesis.
Antenatal diagnosis
Ultrasonographic screening can detect unilateral MCDKs from midway through gestation.
Genetic counseling
Both sporadic and familial cases have been observed. In familial cases, transmission is autosomal dominant with a recurrence risk of 50%.
Management and treatment
Partially based on the supposed increased risk of hypertension and malignancy of which no evidence is found, nephrectomy was performed routinely until recently. Nowadays, in most cases the kidney is left in situ and followed with serial ultrasound. However, nephrectomy may be indicated in case of abdominal obstructive complaints when the cysts become too large. Due to an increased risk of hypertension and/or proteinuria, as a sign of glomerular hyperfiltration or renal dysplasia in the solitary functioning kidney, individuals with unilateral MCDK deserve long-term follow-up. Up to 30% of unilateral cases of MCDK may lead to renal failure at the age of 30 years, at which stage renal replacement therapy is necessary.
Prognosis
The prognosis is influenced by the presence of abnormalities in the contralateral kidney.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr M.F. [Michiel] SCHREUDER | ERKNet*

                                * European Reference Network


A rare developmental defect during embryogenesis characterized by unilateral duplication of an eye which may appear as a synophthalmic eye in a single orbit or as two separate unilateral eyes, each in a separate orbit. The malformation is always associated with other anomalies of the central nervous system (such as porencephaly, meningocele, or arachnoidal cysts) and with craniofacial abnormalities. A proboscis is often found. Clinically, moderate mental retardation and epilepsy are typical.


Unilateral polymicrogyria is a cerebral cortical malformation characterized by unilateral excessive cortical folding and abnormal cortical layering. It comprises two sub-types depending on the areas affected: unilateral hemispheric and focal polymicrogyria (see these terms).


A severe congenital cardiac malformation characterized by both atria related entirely or almost entirely to one functionally single ventricular chamber. The clinical manifestations include congestive heart failure, failure to thrive, cyanosis, hypoxemia and neurodevelopmental disabilities.


Unspecified juvenile idiopathic arthritis is a rare, pediatric, rheumatologic disease, a subtype of juvenile idiopathic arthritis (JIA) characterized by arthritis of an unknown cause that persists for at least 6 weeks, and does not fulfill the criteria for any of the other JIA subtypes, or fulfills criteria for more than one of the other subtypes.


A rare hemoglobinopathy characterized by variable degrees of hemolytic anemia, depending on the nature of the hemoglobin variant. In symptomatic patients, clinical manifestations are jaundice, splenomegaly, and, in patients with severe anemia, pallor. Additional features include reticulocytosis, presence of Heinz bodies, and pigmenturia.


A rare primary bone dysplasia characterized by Perthes-like pelvic anomalies (premature closure of the capital femoral epiphyses and widened femoral necks with flattened femoral heads), arthralgias of hips and knees, and occurrence of enchondromata and ecchondromata. There have been no further descriptions in the literature since 1971.


Upper limb defect-eye and ear abnormalities syndrome

A rare multiple congenital anomalies syndrome characterized by upper limb defects (hypoplastic thumb with hypoplasia of the metacarpal bone and phalanges and delayed bone maturation), developmental delay, central hearing loss, unilateral poorly developed antihelix, bilateral choroid coloboma and growth retardation.


Upper limb mesomelic dysplasia, type Fryns

A rare primary bone dysplasia characterized by isolated upper limb mesomelic dysplasia. Patients present with ulnar hypoplasia with severe radial bowing, but normal stature.


A rare urinary tract tumor characterized by a malignant neoplasm arising from urothelial cells of the pyelocaliceal cavities and ureter. The tumor may be multifocal and bilateral in some cases and is more common in males than in females. Cigarette smoking and occupational exposure are major risk factors. Patients most commonly present with visible or non-visible hematuria and/or flank pain due to obstruction of the flow of urine by tumor tissue, or (less often) to local tumor growth. Systemic symptoms such as anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough can be associated with advanced stages.


Urachal cyst is a congenital urachal anomaly (see this term) characterized by a failure of complete closure of the urachus, in which both ends are closed but the central lumen remains patent. It is typically asymptomatic but may become clinically significant when infected, presenting as a mass in the umbilical region accompanied by abdominal pain and fever.


Urachal diverticulum is the rarest type of congenital urachal anomaly (see this term) resulting from the failure of the distal urachus to close at its point of connectivity to the bladder that is usually asymptomatic but can be associated with recurrent urinary tract infections and other complications.


Urachal sinus is a type of congenital urachal anomaly (see this term) resulting from the failure of the umbilical end of the urachus to close, without continuity to the bladder, and that is usually asymptomatic but can present with continuous cloudy umbilical discharge, tender midline infraumbilical mass and fever when infected.


A rare syndromic intellectual disability characterized by intellectual deficit, short stature, obesity, genital abnormalities, and hand and/or toe contractures. The patients also present with generalized osteoporosis and a history of frequent fractures. This syndrome is similar to Prader-Willi syndrome, but the hand contractures and osteoporosis, together with the lack of hypotonia, indicate this is a different entity.


A rare histidine metabolism disorder characterized by urocanic aciduria and other variable manifestations including intellectual deficit and intermittent ataxia.


A rare syndromic urinary tract malformation characterized by the association of severe voiding dysfunction and inversion of facial expression when the child smiles or cries.

Summary:
Epidemiology
The prevalence of the syndrome is not known; more than 150 cases, mostly children, have been reported. The majority of cases reported in the literature are from Columbia, although affected families have also been reported worldwide.
Clinical description
Patients present with incontinence, urinary tract infections and hydro-uretero-nephrosis with progressive renal impairment. Voiding dysfunction is the result of an obstructive uropathy. About two-thirds of the patients have moderate to severe constipation. Cryptorchidism has also been reported. The peculiar facial dysmorphism is related to an unusual inversion of facial expression that occurs when the child smiles or cries. Nocturnal lagophthalmos has recently been described.
Etiology
The disorder is due to recessive mutations in either HPSE2 (10q23-q24) encoding inactive heparanase-2, or LRIG2 (1p13.2) encoding leucine-rich repeats and immunoglobulin-like domains protein 2; however, in up to 16% of patients, no associated mutations have been found.
Diagnostic methods
No formal diagnostic criteria have been published. Diagnosis may be suspected following recognition of the peculiar facial expression during infancy. Ultrasonography, renal scan, voiding cystourethrogram and urodynamics can be used to evaluate the lower urinary tract dysfunction. A genetic diagnosis can be made through different tests including assessment of a single-gene testing (HPSE or LRIG2 gene), exome or genome sequencing.
Differential diagnosis
Differential diagnoses include Hinman-Allen syndrome (a rare voiding disorder of the bladder of neuropsychological origin), neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida), vescicoureteric reflux, and urethral obstruction.
Antenatal diagnosis
The disorder can be suspected prenatally on ultrasound findings of megabladder, hydroureter, and/or hydronephrosis. However, not all patients will have prenatal manifestations as the onset of symptoms can occur in infancy or even adulthood. Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family.
Management and treatment
Treatment is symptomatic and involves bladder re-education, antibiotic prophylaxis, anticholinergic therapy and alpha-blockers. Intermittent catheterization may be needed. Constipation should be treated. Early diagnosis and treatment are essential in order to prevent upper urinary tract deterioration and renal failure.
Prognosis
Patients live a normal lifespan. Prognosis depends on the severity of the renal disease and precocity of treatment but is generally good, particularly if appropriate treatment is provided and established early.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Dr Camilla MEOSSI  - Dr Donatella MILANI | ITHACA* -  Dario MINOLI | EUROGEN*

                                * European Reference Network


A rare ciliopathy characterized by profound congenital deafness, retinitis pigmentosa and vestibular dysfunction. Retinitis pigmentosa results in visual loss and generally manifests as night blindness, progressively constricted visual fields, and impaired visual acuity. Vestibular dysfunction a defining feature of this form, manifests as delayed motor development with affected infants taking longer to sit independently and to walk. Later on, vestibular dysfunction results in difficulty with activities requiring balance.


A rare ciliopathy characterized by congenital moderate-to-severe deafness, retinitis pigmentosa developing in the first or second decade, and normal vestibular function. Congenital bilateral sensorineural hearing loss is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Additional manifestations include night blindness, constricted visual field (tunnel vision), and later on decreased visual acuity sometimes ending with bare light perception.


A rare ciliopathy characterized by progressive hearing and visual loss in the first decades of life and, in some cases, vestibular dysfunction. Patients have normal hearing at birth. Onset of hearing loss is usually in late childhood or adolescence after development of speech. Profound deafness is mostly reported by middle age. Retinitis pigmentosa related visual loss also develops in late childhood or adolescence. Developmental motor milestones are generally normal but vestibular dysfunction may occur in adulthood.


A rare ciliopathy characterized by congenital or childhood onset sensorineural hearing loss (HL) and retinitis pigmentosa (RP) that occurs in a second step with a night blindness and a progressive vision loss and, in some cases, vestibular dysfunction.

Summary:
Epidemiology
Prevalence of Usher syndrome (US) is estimated at 1/30,000. It is by far the most common cause of hereditary, combined deafness-blindness.
Clinical description
Sensorineural hearing loss is typically congenital and three clinical entities have been defined according to severity of hearing loss severity. Type 1 (around 40% of cases) is characterized by profound, nonprogressive congenital deafness, typically associated with vestibular areflexia that leads to delayed acquisitions (delayed head control, unassisted sitting and walking). Type 2 (around 60% of cases) is characterized by moderate or severe, congenital hearing loss that is slowly progressive and not associated with vestibular disorders. Type 3 (< 3% of cases, but more frequent in the Finnish and Ashkenazi Jewish populations) is characterized by rapidly progressive hearing loss that is often diagnosed during the first decade; vestibular disorders are associated with half of the cases. Retinitis pigmentosa appears later, mainly in the second or third decades, with characteristic night vision and progressive peripheral visual field impairment. Night blindness can be noted in early childhood. The only reported retinal phenotype is rod cone dystrophy. A central visual impairment can be caused by a macular edema. A cataract is frequently observed before the age of 50 years.
Etiology
So far, mutations in five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) have been implicated in USH type 1. Mutations in three genes (USH2A, ADGRV1 and WHRN) have been implicated in USH type 2. Mutations in a predominant gene (CLRN1) have been identified for USH type 3. Some genes are called into question: CIB2 and PDZD7 seem eventually to be involved in non syndromic HL.
Diagnostic methods
Clinical diagnosis is based on findings of a bilateral sensorineural hearing loss associated with a retinitis pigmentosa defined by a night blindness and a peripheral visual field impairment. Multimodal imaging with color, fundus autofluorescence frames (FAF), spectral domain-optical coherence tomography and full-field electroretinogram are required to confirm the diagnosis of rod cone dystrophy. Genetic testing is feasible now based on massively parallel sequencing (gene panels or exomes).
Differential diagnosis
Differential diagnoses include oculo-acoustic syndromes associated with peroxysomal gene alterations (Heimler syndrome with enamel dysplasia), metabolic genetic inherited diseases (Refsum disease), moderate forms of Alstrom syndrome, or mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome). Mutations in TUBB4B gene can cause a dominant inherited oculo-acoustic phenotype, Leber congenital amaurosis and early-onset HL. In some patients, HL can coexist independently of RP.
Antenatal diagnosis
Prenatal diagnosis is feasible for families in which the disease-causing mutations have already been identified.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is straightforward but patients should be informed that heterozygous USH2A mutations are relatively frequent in the general population.
Management and treatment
Management requires a multidisciplinary team with experience in the management of combined deafness and blindness (ENT specialist, ophthalmologist, speech therapist, psychologist, hearing aid specialist, occupational therapist, and all professionals implicated in adapted learning programs for patients with both hearing and visual deficits). Conventional hearing aids may be indicated for patients wit h moderate or severe hearing loss. Cochlear implants, (in most cases bilateral), are now more frequently used for patients with profound congenital hearing loss. Both cochlear implants and hearing aids are more effective when implemented early. Lenses with specialized filters may be recommended for the management of the rod cone dystrophy. A specific treatment with anhydrase carbonic inhibitor can be indicated in case of macular edema. Cataract surgery can be required. Current research is directed towards gene therapy, antisense oligonucleotide therapy (USH2A), neuroprotection and artificial vision systems.
Prognosis
The prognosis mainly depends on the progression of rod cone dystrophy: a severe visual impairment occurs between 50 and 70 years of age in most cases.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Catherine BLANCHET  - Pr Isabelle MEUNIER  - Dr Anne-Françoise ROUX


A rare genetic neurological disorder characterized by severe pseudo-TORCH syndrome with signs of brain damage and occasionally systemic manifestations resembling the sequelae of congenital infection, but in the absence of an infectious agent. Characteristic features include microcephaly, white matter disease, cerebral atrophy, cerebral hemorrhage, and calcifications, among others. Affected individuals typically have seizures and respiratory insufficiency and die in infancy.


A rare, non-syndromic, uterovaginal malformation characterized by variable degrees of cervical aplasia, ranging from complete agenesis to the presence of a cervix with a cervical canal that contains a blind end. Patients typically present primary amenorrhea, cyclical abdominal or pelvic pain, dyspareunia and/or reproductive problems.


A rare congenital urogenital tract malformation characterized by a small uterus of regular shape (simple uterine hypoplasia), an elongated uterus with normal fundus (elongated uterine hypoplasia), or an abnormally shaped uterus (malformative uterine hypoplasia). Symptoms may include primary amenorrhea, abdominal pain, and infertility.


A rare photodermatosis characterized by cutaneous photosensitivity and slight dyspigmentation, without an increased risk of developing skin tumors. Telangiectasia may also be observed, but no other clinical abnormalities. Patients present in infancy or childhood, mode of inheritance is autosomal recessive.


Uveal coloboma-cleft lip and palate-intellectual disability

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula, hearing impairment, and intellectual disability. The spectrum of eye involvement is also variable and includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment.


Uveal melanoma is a rare tumor of the eye, arising from the choroid in 90% of cases and from the iris and ciliary body in the other 10% of cases, which clinically presents with visual symptoms (including blurred vision, photopsia, floaters, and visual field reduction), a visible mass and pain. Fatal metastatic disease is seen in about half of all patients, with the liver being the most frequent site of metastasis.


A rare multiple congenital anomalies characterized by the association of Vertebral anomalies, Anal atresia, Congenital cardiac disease, Tracheoesophageal fistula, Renal anomalies, and Limb defects (acronym VACTERL) with hydrocephalus. Association with hydrocephalus is relatively rare, may be distinct from VACTERL association in general, and may follow an autosomal recessive pattern of inheritance in some individuals.


A rare multiple congenital anomalies characterized by the presence of at least three of the following malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities.

Summary:
Epidemiology
Exact prevalence and incidence data are not available due to variable diagnostic criteria, but the association has been reported to occur in 1-9/100,000 infants, and the annual incidence has been reported to be 1/10,000 to 1/40,000 live births. No specific geographic distribution or predominance in certain populations has been found.
Clinical description
A cluster of congenital malformations may be found prenatally, perinatally, or sometimes later in life, and is usually considered to include at least three component features: vertebral defects (60-80% of patients), commonly accompanied by rib anomalies; imperforate anus/anal atresia (55-90%); cardiac defects (40-80%); tracheo-esophageal fistula (50-80%), with or without esophageal atresia; renal anomalies (50-80%) including renal agenesis, horseshoe kidney, and cystic and/or dysplastic kidneys; and limb abnormalities (40-50%). Limb defects are classically defined as radial anomalies, including thumb aplasia/hypoplasia, and have variable degrees of severity; other types of limb anomalies have also been reported. While the above malformations are considered to be the core component features (some experts consider trachea-esophageal fistula and anal atresia to be especially characteristic), many other malformations have been described in affected patients. These non-typical malformations should be used as clues in considering other possible conditions.
Etiology
VACTERL/VATER association can occur due to a variety of genetic and non-genetic causes, and there are many syndromes with overlapping features. In most individuals, the cause is unknown and the association largely occurs sporadically.
Diagnostic methods
Diagnosis of VACTERL/VATER association is based on the clinical manifestations, which may be evident prior to or after birth.
Differential diagnosis
Differential diagnosis, depending on the overall presentation, includes Baller-Gerold syndrome, CHARGE syndrome, congenital vertebral-cardiac-renal anomalies syndrome, Currarino disease, 22q11.2 microdeletion syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral spectrum, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus, as well as other conditions.
Antenatal diagnosis
The condition may be suspected prenatally, primarily based on prenatal imaging results.
Genetic counseling
The condition most commonly occurs sporadically, and the underlying causes are not known in most individuals. However, the differential diagnosis is broad, and some conditions with features of VACTERL/VATER association have known inheritance patterns.
Management and treatment
Management typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations.
Prognosis
If optimal surgical correction is achievable, the prognosis can be relatively good, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment, though some conditions with overlapping features can include neurologic (and other) findings.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr Benjamin SOLOMON


Vacuolar myopathy with sarcoplasmic reticulum protein aggregates

A rare, genetic vaculolar myopathy characterised by mild myopathy or elevated levels of creatine kinase in the blood without associated symptoms.


A rare vaginal malformation characterized by congenital uterovaginal outflow tract obstruction due to failure of the urogenital sinus to form the caudal aspect of the vagina, which is then replaced by fibrous tissue. The malformation may occur as an isolated developmental defect or in association with other anomalies, such as cervical agenesis, imperforate hymen, and bicornuate bicervical uterus. Presenting signs and symptoms include primary amenorrhea, cyclic pelvic pain, abdominal pain, dyspareunia, pelvic mass, menstrual disorder, and periodic fever.


A group of rare vaginal tumors comprising HPV-associated and HPV-independent squamous cell carcinoma, glandular tumors (including HPV-associated adenocarcinoma, endometrioid carcinoma, clear cell carcinoma, gastric type and intestinal type mucinous carcinoma, and mesonephric adenocarcinoma), adenocarcinoma of Skene gland origin, adenosquamous carcinoma, and adenoid basal carcinoma. Depending on the type of tumor and disease stage, patients may present with symptoms related to a vaginal mass, vaginal bleeding and/or discharge, postcoital bleeding, urinary symptoms, pelvic pain, and a foreign body sensation within the vagina.


A rare X-linked syndromic intellectual disability characterized by intellectual deficit, choroideremia, horizontal nystagmus, severe myopia, acrokeratosis verruciformis-like skin abnormality, anhidrosis, and scapular winging. There have been no further descriptions in the literature since 1959.


Van den Ende-Gupta syndrome is a very rare syndrome characterized by blepharophimosis, arachnodactyly, joint contractures, and characteristic dysmorphic features.

Summary:
Epidemiology
Ten cases from seven families have been reported in the literature.
Clinical description
The dysmorphic features include narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, blepharophimosis, large ears and high-arched or cleft palate. The affected patients can have learning disabilities.
Genetic counseling
The condition is transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


Van der Woude syndrome (VWS) is a rare congenital genetic dysmorphic syndrome characterized by paramedian lower-lip fistulae, cleft lip with or without cleft palate, or isolated cleft palate.

Summary:
Epidemiology
The disorder represents the most common single-gene cause of cleft lip/cleft palate, i.e. 2% of all individuals with cleft lip/palate. Estimated incidence at birth is between 1/35,000 and 1/100,000 in European and Asian populations. Males and females are affected equally.
Clinical description
At birth, patients with VWS have one or more of the following dysmorphic features: paramedian lower-lip pits (fistulae, usually bilateral), small mounds with a sinus tract leading from a mucous gland of the lip, or cleft lip/cleft palate. Lip pits are the most common sign (>80%) and are mostly asymptomatic although dribbling and infection is possible. The second most frequent sign is cleft lip, followed by cleft palate, with variable clinical repercussions depending on severity. Some patients have cleft lip with or without cleft palate, while others have cleft palate only. Hypodontia and dental hypoplasia are also common. Other non-classic signs include single unilateral lip pits, submucous cleft, bifid uvula, ankyloglossia, limb abnormalities (skin folds, syndactyly), and sensorineural hearing loss. Growth, development and intellectual abilities are normal in VWS patients.
Etiology
Mutations in the IRF6 gene (1q32.2-q32.3), involved in epidermal development and in regulation of craniofacial development, are found in over 70% of patients with VWS.IRF6 mutations are also causal for popliteal pterygium syndrome (see this term).Whole-gene deletions are a very rare cause of VWS and the frequency of partial-gene deletions is not currently known. Recently, mutations in the gene GRHL3 (1p36), coding for a Grainyhead-like protein 3 homolog, was found in eight families with VWS with no causative mutations in IRF6.
Diagnostic methods
The diagnosis is suspected on the basis of clinical findings and can be confirmed by molecular genetic testing of IRF6. The presence of isolated lip pits, submucous cleft palate, and hypodontia in a parent of a patient with suspected VWS is highly indicative of the diagnosis.
Differential diagnosis
The main differential diagnosis is autosomal dominant popliteal pterygium syndrome (PPS; see this term). VWS has a milder phenotype; PPS includes popliteal pterygia, syndactyly, and abnormal external genitalia. There is significant overlap in the craniofacial features of the two syndromes. Other conditions to consider include isolated cleft lip and Kabuki syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible provided that the disease-causing allele has been identified in the family. Cleft lip can be identified late in pregnancy on prenatal ultrasound.
Genetic counseling
VWS is inherited in an autosomal dominant manner. However, penetrance is incomplete and de novo mutations have been reported. Genetic counseling is recommended for affected families.
Management and treatment
In the neonatal period, patients with cleft lip/palate should be monitored for nutritional intake and weight gain. Cleft lip and/or palate should then be managed by a multidisciplinary team with surgical and orthodontic treatment as needed. Speech therapy and audiological evaluation may also be required. Lip pits may be treated surgically for cosmetic purposes and/or to ensure proper lip function.
Prognosis
Successful correction of the congenital malformations is the main prognostic factor.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Dr Olivier ABBO  - Pr Philippe GALINIER


A rare human prion disease characterized by accumulation of abnormal prion protein markedly less protease-resistant than in other prion diseases, depending on the genotype at codon 129 of the prion protein gene. No mutations are found in the coding sequence of the gene. Neuropathological analysis shows spongiform change and prion protein deposition with microplaques in the cerebellum. Patients present with slowly progressive cognitive and motor decline, psychiatric symptoms, ataxia, myoclonus, or tremor, among others. The disease is fatal and transmissible to other individuals.


A rare form of amyloidosis characterized by accumulation and extensive visceral deposition of anamyloidogenic variant of beta 2 microglobulin leading to progressive gastrointestinal dysfunction, Sjögren syndrome and autonomic neuropathy.


A rare acquired human prion disease characterized by a progressive, invariably fatal neuropsychiatric disorder resulting from transmission via consumption of products from prion-diseased cows or via blood transfusion from an affected individual. Patients typically present early psychiatric symptoms (such as depression, anxiety, apathy, withdrawal, and delusions), as well as persistent painful sensory symptoms, ataxia, myoclonus, chorea, or dystonia, and dementia. Brain MRI often shows bilateral FLAIR hyperintensities involving the pulvinar thalamic nuclei. Neuropathological examination reveals spongiform change and extensive deposition of abnormal prion protein with florid plaques throughout the cerebrum and cerebellum.


A rare acute hepatic porphyria characterized by neurovisceral attacks and/or skin lesions.

Summary:
Epidemiology
Its prevalence is around 1/330,000 in European countries. Due to a founder effect, it is much higher in South Africa.
Clinical description
The disease generally manifests after puberty, predominantly affecting women. In 60 % of cases, patients' only symptoms are skin lesions due to photosensitivity (bullous photodermatitis). Lesions predominantly appear on sun-exposed areas (hands, face) and are characterized by the presence of more or less painful bullae, which usually leave hyperpigmented scars. In 20% of cases, patients present with both skin lesions and neurovisceral attacks. Finally, 20% of patients experience only neurovisceral attacks. Neurovisceral attacks can last several weeks and manifest as severe abdominal pain, neurological disorders and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, with nausea, vomiting and severe constipation. Psychological disturbances are variable: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).
Etiology
Variegate Porphyria (VP) is caused by a deficiency in coproporphyrinogen oxidase (PPOX, the penultimate enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the PPOX gene (NM_000309.5) coding for PPOX.
Diagnostic methods
Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attacks) and ALA in urine, and defective PPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the PPOX gene confirms the diagnosis.
Differential diagnosis
Differential diagnoses include acute intermittent porphyria and, particularly, porphyria cutanea tarda. The presence of a fluorometric peak (626-628 nm) in plasma is pathognomonic and allows a definitive diagnosis of variegate porphyria rather than porphyria cutanea tarda.
Antenatal diagnosis
Antenatal diagnosis may be offered to families at risk of homozygous porphyria variegata.
Genetic counseling
Transmission is autosomal dominant and penetrance is incomplete. Genetic counseling is offered to patients and their families, informing them that there is a 50% risk of transmitting the disease at each pregnancy.
Management and treatment
Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of episodes (avoidance of triggers, particularly drugs). Phlebotomy and chloroquine are not effective in treating cutaneous signs. Micro-bleeds are beneficial in some patients. Protecting the skin from light is key. In the case of symptomatic iron-deficiency anemia, iron supplementation is likely to cause a skin flare-up and should preferably be administered intravenously.
Prognosis
Thanks to early diagnosis and management, fatal outcomes from acute attacks are rare. The disease is rarely progressive. On the other hand, VP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


A rare genetic connective tissue disorder typically characterized by the association of unexpected organ fragility (arterial/bowel/gravid uterine rupture) with inconstant physical features as thin, translucent skin, easy bruising and acrogeric traits.

Summary:
Epidemiology
The true prevalence of vascular Ehlers-Danlos syndrome (vEDS) is unknown, due to underdiagnosis of both symptomatic and milder forms of the disease. Prevalence estimates range between 1/50 000 and 1/200 000.
Clinical description
Typical physical signs associated with vEDS are predominantly cutaneous, as easy bruising unrelated to trauma, thin translucent skin predominantly on the upper torso and abdomen, with abnormally visible veins. Wound healing may be delayed and may result in widened, papyraceous scars, particularly over prominent bony pressure points (knee). Extremities, particularly hands may appear prematurely aged (acrogeria). Characteristic facial features are prominent eyes, thin lips, sunken cheeks and a pinched nose. Hair loss, particularly notable in women may also be present. Clinical complications of vEDS typically start to occur in the late teenage years, more rarely during childhood, and may repeat at unpredictable time intervals through the entire adult life. Most common complications are arterial accidents involving medium size arteries, including dissections, aneurysms, arterial rupture and arteriovenous fistulas. Spontaneous carotid-cavernous fistula is almost pathognomic of vEDS. Digestive complications are dominated by spontaneous perforations of the sigmoid colon. Solid organ rupture as liver or spleen, may also occur. Other complications are gravid uterine rupture or arterial rupture in the peripartum period. Spontaneous, often recurrent hemo/pneumothoraces are not uncommon. Varicose veins are also commonly present in vEDS patients at a young age.
Etiology
The disorder is caused by mutations in the COL3A1 gene (2q32.2), which encodes for the pro-alpha1-chains of type III procollagen.
Diagnostic methods
Diagnosis is suspected on the base of physical signs and clinical complications in probands, and requires the identification of a pathogenic variant within the COL3A1 gene by molecular genetic testing (single gene testing or multigene panel including COL3A1).
Differential diagnosis
Main differential diagnosis are other forms of Ehlers-Danlos syndromes, notably classical EDS (including COL1A1 variants leading to substitutions of arginine to cysteine residues in the triple helical domain), kyphoscoliotic EDS and periodontal EDS. Other rare connective tissue disorders are: Loeys-Dietz syndromes, polycystic kidney disease, and Marfan syndrome. In children with marked bruising, coagulation disorders and child abuse are sometimes considered.
Antenatal diagnosis
Preimplantation and prenatal genetic diagnosis can be considered in families where the mutation is known.
Genetic counseling
Half of vEDS patients have inherited the pathogenic variant from an affected parent. The other half of patients have a de novo pathogenic variant, except for rare cases of parental COL3A1 somatic mosaicism. The pattern of inheritance is typically autosomal dominant, and thus there is a 50% risk of transmitting the disease to offspring. Rare cases of biallelic mutations have been reported. Therefore, genetic counseling should be offered to affected families.
Management and treatment
Patient management requires a multidisciplinary care team, ideally in dedicated centers for vEDS patients. These centers coordinate follow-up of clinically silent patients and implement prophylactic measures. Acute onset, unexplained pain require emergency imaging by appropriate means to exclude arterial rupture. Acute arterial complications commonly require hospitalization with a conservative approach in most cases. Life-saving procedures (arterial rupture, bowel perforation, etc.) may require interventional radiology, vascular or bowel surgery. Medical management includes optimal blood pressure control to minimize arterial stress. Betablockers may be of interest in reducing arterial complications, but only one has been investigated in that indication (celiprolol). Angiotensin receptor blockers might also be beneficial and are currently being investigated.
Prognosis
Prognosis is variable and depends in part on the type of pathogenic COL3A1 variant. There is also an important intra- and interfamilial heterogeneity in the age of onset of complications and life expectancy for the same variant. Overall, patients with vEDS are exposed to recurrent organ complications, estimated at a rate of 1.6 events/5 years, 1.3 events/5 years for arterial complications. Overall life-expectancy is reduced to a median 51 years of age, but with an important range in age of survival for individual patients.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Michael FRANK


Vasculitis represents a clinically heterogenous group of diseases of multifactorial etiology characterized by inflammation of either large-sized vessels (large-vessel vasculitis, e.g. Giant-cell arteritis and Takayasu arteritis; see these terms), medium-sized vessels (medium-vessel vasculitis e.g. polyarteritis nodosa and Kawasaki disease; see these terms), or small-sized vessels (small-vessel vasculitis, e.g. granulomatosis with polyangiitis, microscopic polyangiitis, immunoglobulin A vasculitis, and cutaneous leukocytoclastic angiitis; see these terms). Vasculitis occurs at any age, may be acute or chronic, and manifests with general symptoms such as fever, weight loss and fatigue, as well as more specific clinical signs depending on the type of vessels and organs affected. The degree of severity is variable, ranging from life or sight threatening disease (e.g. Behçet disease, see this term) to relatively minor skin disease.


Vasoproliferative tumor of the retina is a rare, benign, retinal vascular disease characterized by solitary or multiple, unilateral or bilateral, intra-retinal tumor(s), usually located in the peripheral infero-temporal quadrant, and often associated with sub- and intraretinal exudates, epiretinal membranes, exudative retinal detachment and cystoid macular edema, as well as, occasionally, retinal and vitreous hemorrhage. Patients may present with visual loss, floaters, and/or photopsia. Association with various conditions, such as retinitis pigmentosa, congenital retinal toxoplasmosis, retinopathy of prematurity, or coloboma, has been reported.


A rare subtype of pyoderma gangrenosum disease characterized by a solitary, erythematous, ulcerated plaque, which lacks the violaceous border typically present in classic pyoderma gangrenosum, usually affecting individuals who are otherwise healthy. Histologically, the lesion presents a central layer containing neutrophilic inflamation, surrounded by a palisade of histiocytes, which are rimmed by a lymphocytic infiltrate. In comparison with the other variants of pyoderma gangrenosum, this subtype usually shows a good response to less aggressive treatments and underlying systemic disorders are less frequently associated. It is considered the most benign and uncommon clinical variant of pyoderma gangrenosum.


A rare intracranial congenital high-flow vascular malformation characterized by arteriovenous shunts draining into the median prosencephalic vein of Markowski, embryonic precursor of the vein of Galen, typically presenting in neonates or infants.

Summary:
Epidemiology
Although its prevalence is unknown, vein of Galen aneurysmal malformation (VGAM) is thought to account for 30% of all pediatric intracranial arteriovenous malformations.
Clinical description
Clinical presentation differs according to age group. Neonates typically present with congestive heart or multi-organ failure and, in more severe cases, melting brain syndrome. Infants tend to present with hydrovenous disorders (hydrocephalus, macrocrania), collateral maxilla-facial venous circulation, neurodevelopmental delays; children (and exceptionally young adults) commonly present with neurological symptoms (seizures, deficit, headaches or intracranial hemorrhage). Pulsatile bruit can be heard at auscultation of the skull. VGAM can be classified into mural or choroidal types based on their angioarchitecture. The mural type occurs when the fistula is in the wall of the dilated vein itself. The choroidal type consists of multiple shunts into choroidal tributaries draining into the prosencephalic vein of Markowski. Mixed forms combining direct shunts and arterial networks may also occur.
Etiology
VGAM is created between the 8th and 11th weeks of gestation. Recent data suggest that genetic dysregulation of RAS signaling pathway is an important driver of VGAM pathogenesis.
Diagnostic methods
Imaging is essential for diagnosis and include trans-fontanel ultrasonography, magnetic resonance imaging/angiography (MRI/MRA) or computed tomography scan, and digital subtraction angiography (usually coupled with embolization).
Differential diagnosis
It is important to differentiate VGAM from dilatation of the vein of Galen draining cerebral arteriovenous malformation (AVMs); venous dilatation without arteriovenous shunt can also be observed in developmental venous anomalies or in rare neonatal cases with congenital cardiopathy. In the assessment of neonatal heart failure, VGAM has to be excluded from congenital cardiopathy.
Antenatal diagnosis
Diagnosis is most often made during the third trimester of pregnancy with ultrasound and fetal MRI.
Genetic counseling
VGAM can occur in the context of capillary malformations AVMs and more rarely in hereditary haemorrhagic telangiectasia. Genetic screening can therefore be proposed to patients depending on the clinical and familial context.
Management and treatment
If the diagnosis is established antenatally, delivery at a tertiary care center is recommended. The timing of endovascular management depends on the clinical presentation. Ideally, the first intervention should be performed at 5-6 months of age; however, early embolization may be required if there is congestive heart failure refractory to medical management or if cerebral development is impaired. In such cases, partial, rather than complete, obliteration of the shunt is the goal in order to improve hemodynamic situation and allow proper maturation of the brain. A residual shunt will be occluded at later times in sequential procedures. Hydrocephalus may require ventriculocisternostomy (preferred to ventricular shunt which is associated with neurological complications) in association with endovascular treatment of the VGAM.
Prognosis
The neurological prognosis can be satisfactory with early proper treatment; however, the prognosis is poorer for patients with severe neonatal presentation or with cerebral defects or cardiac dysfunction detected prenatally. Patients presenting later in life have better post-operative outcomes.

                            Last update:
                            July 2024

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

                                * European Reference Network


A very rare multiple congenital anomalies syndrome characterized by short stature, facial dysmorphism (elongated face, hypertelorism, broad and high nasal bridge, mild epicanthus, posteriorly angulated ears, narrow and high-arched palate), skeletal anomalies (mesomelic brachymelia, short broad hands, prominent finger pads, short stubby thumbs, hyperextensibility of small joints, small feet), hypernasality and normal intelligence. Delayed bone age has also been reported.


Venezuelan hemorrhagic fever (VHF), caused by the Guanarito virus, is a viral hemorrhagic disease characterized by fever, headache, arthralgia, sore throat, convulsions, and hemorrhagic manifestations.


Venous thoracic outlet syndrome (VTOS) is a form of thoracic outlet syndrome (TOS; see this term) that manifests as unilateral (rarely bilateral) arm pain and cyanosis.

Summary:
Epidemiology
Determination of incidence is difficult due to the lack of a confirmatory test for TOS. VTOS accounts for 2%-3% of all cases of TOS.
Clinical description
VTOS occurs in young adults, usually after excessive arm activity. The characteristic symptoms, caused by venous obstruction, are arm swelling, cyanosis, pain and mild paresthesias. Neck pain and headaches may rarely occur. The forearm fatigues within minutes of use. Visible subcutaneous veins over the shoulder and upper chest are often present.
Etiology
Repetitive arm motion and compression of the subclavian vein in the neck (between the clavicle and the first rib) leads to scar tissue that can predispose one to thrombosis due to narrowing of vessels.
Diagnostic methods
Diagnosis is based on findings of arm swelling, cyanosis and distended superficial veins. Radiographs may identify compressive sources including an elongated C7 transverse process or anomalous first rib. Subclavian vein stenosis or occlusion on dynamic ultrasonography, magnetic resonance or computed tomography venography supports the diagnosis. Provocative physical exam maneuvers such as the Roos (test is positive when patient is unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes) and Adson (test is positive if radial pulse disappears while turning the head with extended neck following deep inspiration) tests can also be helpful.
Differential diagnosis
Differential diagnoses include arterial (ATOS) and neurogenic TOS (NTOS) (see these terms), which are differentiated clinically. ATOS presents as upper extremity ischemia due to subclavian artery compression or thrombosis and can be ruled-out with magnetic resonance angiography. True NTOS usually presents as a lower trunk brachial plexopathy and is diagnosed with electrodiagnostics or MRI. Other causes of venous obstruction including tumors, congenital abnormalities and upper extremity deep venous thromboses must also be considered.
Management and treatment
When acute, treatment is thrombolytic therapy followed by decompressive surgery (first rib resection, pectoralis minor release or scalenectomy) to decrease recurrences. Angioplasty or surgical bypass is performed to repair damaged veins. If chronic, with heaviness and a swollen limb but with a patent subclavian vein, decompressive surgery, angioplasty or vascular reconstruction is recommended. Physical therapy is not generally helpful in treating VTOS, but may be helpful in less severe cases.
Prognosis
Patients undergoing successful thrombolysis followed by decompression have five-year secondary vein patency rates greater than 95% but residual edema may limit function.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN


A rare respiratory disorder characterized by major reduction of diaphragmatic contractile force together with fiber atrophy in the diaphragm and other respiratory muscles as a consequence of invasive mechanical ventilation. Reduction of diaphragmatic contractile force may be observed even within hours after intubation. The condition can increase weaning time and affects weaning outcome, mortality, and long-term clinical outcomes.


Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome

This syndrome is characterized by cardiac arrhythmias (ventricular extrasystoles manifesting as bigeminy or multifocal tachycardia with syncopal episodes), perodactyly (hypoplasia and/or agenesis of the distal phalanges of the toes) and Pierre-Robin sequence (see this term).

Summary:
Epidemiology
It has initially been reported in six patients from three generations of one family. Four affected members of another family manifesting a similar constellation of clinical features have recently been reported.
Clinical description
An additional feature may be an antimongoloid slant of the palpebral fissures.
Etiology
Etiology remains unknown.

                            Last update:
                            September 2009


A rare genetic syndrome with a central nervous system malformation as a major feature, characterized by a triad of high alpha-fetoprotein levels in both maternal serum and amniotic fluid, cerebral ventriculomegaly, and renal macro- and microcysts. Variable findings include congenital nephrotic syndrome, aqueductal stenosis, gray matter heterotopias, and cardiac malformations, among others.


Verloove Vanhorick-Brubakk syndrome is a multiple congenital anomalies/dysmorphic syndrome characterized by multiple skeletal malformations (short femora and humeri, bilateral absence of metatarsal and metacarpal bone in hands and feet, bilateral partial syndactyly of fingers and toes or oligopolysyndactyly, deformed lumbosacral spine), congenital heart disease (truncus arteriosus), lung and urogenital malformations (bilateral bilobar lungs, horseshoe kidney, cryptorchidism), and facial malformations (bilateral cleft lip and palate, micrognathia, small, low-set ears without external meatus). It is lethal in the neonatal period. There have been no further descriptions in the literature since 1981.


A rare disorder of the anterior segment of the eye, characterized by a severe recurrent allergic reaction affecting the cornea and the conjunctiva. It presents with red eyes, ocular itching, photophobia, foreign body sensation, mucous discharge, blepharospasm, and blurring of vision. The symptoms are typically bilateral but may be asymmetric. Characteristic signs include conjunctival injection, giant papillae mostly on the upper tarsal conjunctiva (cobblestone appearance), limbal gelatinous infiltrates (Horner-Trantas dots), and variable corneal signs. The condition is more prevalent in hot climates and most commonly affects young boys.


A rare vascular anomaly characterized by congenital, solitary or grouped, red-to-purple plaques which may bleed and enlarge over time. The lesions show a predilection for the lower extremities. Histological examination reveals numerous dilated, congested capillaries and venules in the papillary dermis, often with a deep dermal component, and with increased density of variably congested capillaries and venules also in the subcutaneous tissue. The overlying epidermis displays prominent acanthosis, papillomatosis, hyperkeratosis, parakeratosis, and crusting.