A rare, genetic, intestinal disease characterized by osmotic diarrhea, abdominal pain and increased rectal flatulence after ingestion of trehalose, a disaccharide found mainly in mushrooms, due to intestinal trehalase deficiency. It occurs primarily in the Greenland population, although cases have also been reported elsewhere.


Tremor-nystagmus-duodenal ulcer syndrome is a rare hyperkinetic movement disorder characterized by mild to severe, progressive essential tremor, nystagmus (principally horizontal), duodenal ulceration and a narcolepsy-like sleep disturbance. Refractive errors and cerebellar signs, such as gait ataxia and adiadochokinesia, may be associated. There have been no further descriptions in the literature since 1976.


A rare bacterial infectious disease caused by the louse-borne bacterium Bartonella quintana and characterized by a variable clinical picture with acute or insidious onset of a (potentially relapsing) febrile illness, headache, leg pain (most typically the shinbone), endocarditis, and thrombocytopenia. There may also be only non-specific symptoms that mimic other infections. The disease nowadays most commonly affects socially disadvantaged persons in urban areas.


Trichinellosis is a zoonotic parasitic disease caused by the consumption of raw or undercooked meat (pork and wild game) infected by nematodes of the genus Trichinella and that is characterized by an enteral (intestinal) phase, that can be asymptomatic or that can manifests with diarrhea, nausea, vomiting and abdominal pain, and a parenteral (muscular) phase, manifesting with fever, periorbital edema, muscle swelling and pain, weakness, and in some cases, skin rash and peripheral edema. Rarely, potentially fatal cardiac (i.e. myocarditis), pulmonary (i.e. pneumonitis, respiratory failure), and nervous system (i.e. meningoencephalitis) complications may occur.


Tricho-dento-osseous dysplasia (TDO) belongs to the ectodermal dysplasias and is characterised by curly/kinky hair at birth, enamel hypoplasia with discolouration and molar taurodontism, increased overall bone mineral density (BMD) and increased thickness of the cortical bones of the skull.

Summary:
Epidemiology
The prevalence is unknown but the disease has been described in at least 8 families with over 30 affected members in some large kindreds.
Clinical description
The disease shows significant inter and intrafamilial clinical variation, with enamel hypoplasia and taurodontism being the most consistent features, however, the extent of the enamel defects may also vary between affected family members. The hair and bone manifestations are more variable and age dependent. Curly/kinky hair is present at birth in around 80% of patients, but around half of these patients loose the hair phenotype by adolescence. The BMD measurements show increasing variability with age, particularly in the radius and ulna. In addition, spinal BMD shows an increase with age. Other reported features include flat/brittle fingernails, increased susceptibility for caries and abscesses, delayed dental eruption, tubular sclerosis of the long bones, dolichocephaly (as a result of craniosynostosis), and an absence of mastoid pneumatisation, the frontal sinus and calvarial diploe.
Etiology
The syndrome is caused by mutations in the distal-less homeobox gene (DLX3), located on the long arm of chromosome 17 (17q21.3-q22).
Diagnostic methods
Diagnosis can be made by clinical and radiological examination and confirmed by detection of DLX3 mutations.
Differential diagnosis
The differential diagnosis should include amelogenesis imperfecta, hypomaturation-hypoplastic type, with taurodontism (AIHHT), oculodentoosseous dysplasia (see this term) and the autosomal dominant form of osteopetrosis (see this term).
Genetic counseling
The disease is transmitted as a highly penetrant autosomal dominant trait.
Management and treatment
Treatment is symptomatic and patients require frequent dental follow-up.
Prognosis
The prognosis is good and there appearsto be no predisposition for developing fractures.

                            Last update:
                            January 2007


Tricho-retino-dento-digital syndrome is an autosomal dominant ectodermal dysplasia syndrome, characterized by uncombable hair syndrome (see this term), congenital hypotrichosis and dental abnormalities such as oligodontia (see this term) or hyperdontia, and associated with early-onset cataract, retinal pigmentary dystrophy, and brachydactyly with brachymetacarpia. Furthermore, hyperactivity and a mild intellectual deficit have been reported in affected patients.


A rare ectodermal dysplasia syndrome characterized by the association of sparse, fine, dry, slow growing hair with variable dental abnormalities including oligodontia, peg-shaped incisors, and shell teeth. Mild intellectual disability, microcephaly, and dysmorphic facial features have also been reported.


Trichodermodysplasia-dental alterations syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by sparse, thin, brittle scalp hair, as well as sparse eyebrows, eyelashes, axillary and pubic hair, delayed eruption of deciduous teeth and hypodontia of both dentitions. Mild palmoplantar keratosis, café-au-lait spots on back, mild dystrophy of nails, and tibial deflection of toes are also associated. There have been no further descriptions in the literature since 1986.


A rare ectodermal dysplasia syndrome characterized by the association of amelogenesis imperfecta and trichodysplasia with symmetrical pits in the cuticles of hair shafts. There have been no further descriptions in the literature since 1993.


Trichodysplasia-xeroderma syndrome is an extremely rare, syndromic hair shaft anomaly characterized by sparse, coarse, brittle, excessively dry and slow-growing scalp hair, sparse axillary and pubic hair, sparse or absent eyelashes and eyebrows and dry skin. Hair shaft analysis shows pili torti, longitudinal splitting, grooves, peeling and scaling. There have been no further descriptions in the literature since 1987.


A rare benign follicular hamartoma that develops primarily on the face of adults, with a particular predilection for the back of the nose, but also on the neck or scalp. It presents as a solitary hemispheric flesh-colored nodule with a central pore or black dot that may contain a tuft of hair.


Trichomegaly-retina pigmentary degeneration-dwarfism syndrome, also known as Oliver-McFarlane syndrome, is an extremely rare genetic disorder characterized by hair abnormalities, severe chorioretinal atrophy, hypopituitarism, short stature, and intellectual disability.


Trichoodontoonychial dysplasia is a rare ectodermal dysplasia syndrome characterized by severe generalized hypotrichosis, parietal alopecia, secondary anodontia resulting from enamel hypoplasia, onychodystrophy, bone deficiency in the frontoparietal region and skin manifestations (incl. nevus pigmentosus, papules, ephelides, palmoplantar keratosis, supernumerary nipples, abnormal dermatoglyphics). There have been no further descriptions in the literature since 1983.


A rare multiple congenital anomalies syndrome characterized by short stature, sparse and depigmented scalp hair, typical facial characteristics (broad eyebrows, especially the medial portion, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears), and limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia).

Summary:
Epidemiology
The exact prevalence is unknown. Around 250 cases have been published in the world literature. The disease is infrequently described as mildly affected individuals may go unnoticed.
Clinical description
The disease has variable severity and clinical presentation, even between family members. It presents typically with prenatal and postnatal growth delay. The facial characteristics (broad eyebrows, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears) may be noticeable early on but may also remain completely unnoticed, especially as some features such as thin and sparse scalp hair are also common in infants in the general population. As time passes, growth delay, accompanied by increasing hair loss and dental overcrowding, may make the facial features more apparent. The brachydactyly also becomes more visible. Fingers start to deviate due to epiphyseal abnormalities in childhood which continues till adulthood. Increased and/or decreased mobility in the finger joints can occur and may cause pain. Hips abnormalities and associated pain are very common; they may present sometimes in late childhood but almost invariably in adulthood. Radiology typically reveals joint dysplasia, reduced joint space and sclerotic bone. Distal limb mobility problems often develop at a later age. Hip problems can be so severe that hip replacement may be indicated in early adulthood. The term "trichorhinophalangeal syndrome type 3'' has previously been used to refer to a severe form of type 1 with pronounced facial characteristics, short stature and brachydactyly.
Etiology
TRP type 1 is caused by heterozygous pathogenic variants in TRPS1 (8q23.3). Infrequently, inversions and balanced translocation disrupting the function of TRPS1 have been reported. Pathogenic variants are considerably different in type and location, with no clear genotype-phenotype correlation. TRPS1 is a zinc finger transcriptional repressor involved in regulating growth and development of chondrocytes and perichondrium.
Diagnostic methods
Diagnosis is typically suspected on clinical presentation and confirmed by genetic testing with sequencing technology.
Differential diagnosis
The differential diagnosis includes other disorders in which ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose such as oculodentodigital dysplasia, cartilage-hair hypoplasia, and Ellis-Van Creveld syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Families should be aware that intra-familial variety in severity can be marked, and the severity of the phenotype cannot be predicted by prenatal testing.
Genetic counseling
The disorder is autosomal dominant with full penetrance. Whilst most cases occur sporadically, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Germline mosaicism has been detected in rare cases.
Management and treatment
The management and treatment are mostly supportive. Ectodermal manifestations of hair, nails and teeth can be managed with esthetic care such as the use of wigs, artificial nails, and extraction of supernumerary teeth. In patients whose growth hormone stimulation tests results are subnornal or abnormal, growth hormone therapy can be considered and may (variably) result in increased growth in height. Physiotherapy and occupational therapy can be beneficial for problems of altered distal limb mobility. Regular simple analgesics (such as NSAID) may be used to treat joint pain. Prosthetic hip implantation should be considered in individuals with severe hip dysplasia, even in early adulthood. If osteopenia is present, bisphosphonates may be considered.
Prognosis
Life expectancy is normal. The unusual facial morphology and ectodermal manifestations, combined with the reduced mobility, can have a marked impact on the quality of life. Peer support and counseling by a social scientist can be beneficial.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM | ITHACA* - Dr S.M. [Saskia] MAAS | ITHACA*

                                * European Reference Network


A rare multiple congenital anomalies syndrome characterized by intellectual disability, short stature, sparse and depigmented scalp hair, typical facial characteristics (broad eyebrows, especially the medial portion, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears), limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia) and multiple cartilaginous exostoses.

Summary:
Epidemiology
The prevalence is unknown. Around 100 cases were described in the literature.
Clinical description
The disease has variable severity and clinical presentation. The disorder goes along with prenatal and postnatal growth delay which can be the presenting clinical sign. Although the typical facial characteristics are present from early on, they may go unnoticed as facial morphology may differ only mildly from a typical face; thin and sparse scalp hair are also common in infants in the general population. Microcephaly is present in more than half of the affected individuals. Delayed motor and cognitive development is usually the reason for further investigations; this may lead to a decreased ability of the affected individuals to indicate joint problems of the distal limbs and hips, which are however present in a similar way as in trichorhinophalangeal syndrome (TRPS) type 1. The developmental delay vary and may be mild or marked. Multiple exostoses arise in the first five years of life, especially on the limbs but potentially also elsewhere, and become more marked with time. Exostoses may lead to bone deformation, pain, and functional problems. Malignancies are extremely uncommon.
Etiology
TRPS type 2 is caused by a microdeletion in chromosome 8q23.3-q24.11 leading to the loss of the genes TRPS1, RAD21 and EXT1 and is therefore a contiguous gene syndrome. Usually the microdeletion occurs de novo but some inherited cases have been reported. A small number of affected individuals have a deletion which involves only RAD21 and EXT1; in these patients, the facial characteristics are similar to those of Cornelia de Lange syndrome. TRPS1 is a zinc finger transcriptional repressor involved in growth regulation and the development of chondrocytes and perichondrium.
Diagnostic methods
Diagnosis is typically suspected on clinical presentation and confirmed by genetic testing through chromosomal microarray analysis.
Differential diagnosis
TRPS type 2 needs to be distinguished from other disorders in which intellectual disability and ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose. The phenotype of TRPS type 2 is very characteristic and is usually not confused with any other disorder, except for patients in whom the microdeletion does not involve TRPS1, who may resemble patients with Cornelia de Lange syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible if the pathogenic variant has previously been identified in the affected family member. Parental germline mosaicism has not been reported but remains theoretically a possibility.
Genetic counseling
The disorder is autosomal dominant. Most cases occur sporadically. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Penetrance has been 100% in all reported individuals to date. Somatic mosaicism is extremely uncommon.
Management and treatment
Ectodermal manifestations and growth delay are cared for in the same way for individuals both with TRPS type 1 and TRPS type 2, and take into account the developmental level of the affected individual. In patients with a marked developmental disability, joint issues and pain need to be considered as affected individuals may be unable to indicate these by themselves. Exostoses need regular follow-up by an orthopedic specialist, and should be treated in the same way as in those with isolated multiple exostoses.
Prognosis
Life expectancy is normal. The reduced mobility and developmental problems can have a major impact on the quality of life.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM | ITHACA* - Dr S.M. [Saskia] MAAS | ITHACA*

                                * European Reference Network


A rare, genetic, syndromic hair shaft abnormality disorder characterized by short, dry, sulfur-deficient, brittle hair usually associated with highly variable neuroectodermal manifestations, such as ichthyosis, photosensitivity, and intellectual disability.

Summary:
Epidemiology
Although epidemiological data is limited worldwide, the prevalence at birth has been estimated at 1/830,000 in Europe.
Clinical description
TTD syndromes are numerous syndromes affecting mainly organs derived from the neuroectoderm. The clinical appearance is always characterized by brittle and fragile hair, often combined with congenital ichthyosis and nail abnormalities, growth retardation and intellectual deficit among other symptoms. The abnormalities are generally present at birth, with variable clinical expression. About half of the patients with TTD exhibit marked photosensitivity, due to abnormalities in excision repair of ultraviolet (UV)-damaged DNA. In these patients, the deficiency in DNA excision repair is indistinguishable from that observed in Xeroderma Pigmentosum type D (due to ERCC2 variants), however TTD patients do not have an increased risk of skin cancers.
Etiology
Patients with a photosensitive form of TTD carry biallelic mutations within three genes encoding distinct subunits of the multi-protein transcription initiation factor IIH (TFIIH) complex, including most frequently ERCC3, but also GTF2H5 or ERCC2. TFIIH is essential for both transcription initiation and nucleotide excision repair (NER). Seven genes have been identified in the so-called non-photosensitive form of TTD, which encode M-phase-specific PLK1 interacting protein (encoded by MPLKIP), general transcription factor IIE subunit 2 (GTF2E2), the X-linked ring finger protein 113A (RNF113A) and the recently identified cysteinyl-tRNA synthetase (CARS), threonyl-tRNA synthetase 1 (TARS1), alanyl-tRNA synthetase (AARS1) and methionyl-tRNA synthetase (MARS1).
Diagnostic methods
The diagnostic findings of TTD are short, unruly, brittle hair, with alternating dark and light bands under polarizing microscopy (tiger-tail pattern), trichoschisis (or trichorrhexis), and an absent or defective cuticle visualized by scanning electron microscopy. The amino-acid analysis of hair shafts revealed a cystine content commonly reduced to less than half of normal values. Functional testing (Unscheduled DNA synthesis) of the nucleotide excision repair system may help to identify photosensitive forms harboring DNA repair defect activity. The diagnosis may be confirmed molecularly.
Differential diagnosis
TTD is a differential diagnosis in congenital alopecias.
Antenatal diagnosis
Antenatal molecular diagnosis is possible only if the molecular diagnosis is made in the index case.
Genetic counseling
All forms of TTD are autosomal recessive disorders except for one X-linked form.
Management and treatment
There is no specific treatment. Patients should receive regular follow-ups in order to precociously detect any neurological, skin, growth delay, malformation and/or immune deficiency. Early intervention with a multidisciplinary team involving pediatricians, neurologists, physiotherapists, psychologists benefit development of the infant and quality of life. Management of ichthyosis is non-specific and mostly relies on topical application of ointments and keratolytic agents. Photoprotection is mandatory in photosensitive forms of TTD.
Prognosis
Severe infections may account for the premature death in patients with TTD, who have a higher mortality compared to the general population.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Dr Fanny MORICE-PICARD | ERN-Skin*

                                * European Reference Network


A rare congenital heart malformation characterized by absence of the tricuspid valuvar annulus (absent right atrioventricular connection/junction) or an imperforate tricuspid valve leading to severe hypoplasia of right ventricle (functionally univentricular heart). The malformation is associated with normally related great arteries (70 to 80% of cases) or transposed great vessels, an obligatory interatrial connection that is crucial for survival (patent oval foramen or atrial septal defect ostium secundum type), ventricular septal defect (VSD), pulmonary outflow obstruction (pulmonary atresia, stenosis or hypoplasia), aortic coarctation and/or aortic arch interruption.

Summary:
Epidemiology
In Europe, the prevalence at birth ranges between 1/11,000-50,000. Tricuspid atresia accounts for around 1% of all congenital heart defects. Both sexes are equally affected.
Clinical description
At least 80% of children born with tricuspid atresia are symptomatic during the first month of life. Two main clinical presentations are observed, depending on the anatomy: patients with high pulmonary blood flow, and patients with reduced pulmonary blood flow. Subpulmonary obstruction is due to a restrictive VSD when ventriculo-arterial connections are concordant. Patients with high pulmonary blood flow can have either concordant or discordant ventriculo-arterial connections. In the latter case, coarctation of the aorta can occur if the VSD is restrictive. These patients develop cardiac failure, failure to thrive and recurrent upper respiratory tract infections. Patients with reduced pulmonary blood flow exhibit cyanosis and tachypnea without signs of heart failure.
Etiology
Etiology is still largely unknown. Tricuspid atresia results from an arrest in cardiac development at an early stage, when the atrioventricular canal is supported only by the primary (left) ventricle and there is no connection between the right atrium and the developing right ventricle. Tricuspid atresia is found in chromosomal anomalies such as 22q11, 4q31, 8p23 and 3p microdeletions. Some genes have been recognized as potentially involved: ZFPM2, HEY2, NFATC1, NKX2.5, and MYH6. Tricuspid atresia has also been reported in association with Alagille and Ellis Van Creveld syndromes.
Diagnostic methods
Diagnosis is suspected on clinical examination of cyanosis and heart murmur, and is confirmed on cross-sectional echocardiography. Echocardiography will assess the position of the great vessels, transposed or not, the magnitude of the shunt between the ventricles and the atria, and the presence of subpulmonary stenosis or coarctation, allowing to plan surgical management.
Differential diagnosis
Differential diagnosis includes all cyanotic congenital heart defects and non-cardiac causes of neonatal cyanosis in forms with reduced pulmonary blood flow, and other causes of high pulmonary blood flow. It also includes other univentricular hearts.
Antenatal diagnosis
Like all other types of univentricular hearts, the prenatal detection rate of tricuspid atresia is high (between 70 and 90%) in countries with antenatal screening policies implemented.
Genetic counseling
Most cases of tricuspid atresia occur sporadically as a result of spontaneous genetic mutations. The recurrence risk for tricuspid atresia is low, 1%.
Management and treatment
The management of neonates with tricuspid atresia depends on the pulmonary blood flow. If pulmonary blood flow is high, pulmonary banding will be indicated to protect the pulmonary vascular bed. If it is reduced, prostaglandin E1 may be needed to maintain the permeability of the arterial duct before a surgical Blalock-Taussig-Thomas systemic-to-pulmonary anastomosis is performed. Rashkind maneuver may be needed if the interatrial shunt is restrictive. The second surgical stage will consist of a partial cavopulmonary connection (superior caval vein to pulmonary artery anastomosis) between 4 and 6 months of age, followed by the Fontan procedure (total cavopulmonary connection, fenestrated or not) between 2 and 4 years of age.
Prognosis
Fontan procedure is a palliative surgery which does not restore a biventricular circulation. Current pooled survival estimates at 5, 10 and 15 years are 88.4%, 85.7% and 84.1% respectively. Long-term complications include left ventricular dysfunction, atrial arrhythmias, cardiac conduction disorders, thromboembolism, cirrhosis and hepatocellular carcinoma, and protein-losing enteropathy. Many of these patients will ultimately require cardiac transplantation.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


A rare, congenital, non-syndromic heart malformation characterized by partial or complete absence of tricuspid valve tissue and its apparatus, with an existing orifice. It can be isolated or associated with other heart anomalies. Clinical presentation is variable and may include syncope, arrhythmias, cyanosis, right heart dilatation and failure.


A rare acquired peripheral neuropathy characterized by paroxysmal, sharp, stabbing, electric-shock-like orofacial pain, that is restricted to one or more of the trigeminal nerve divisions and mostly unilateral. Attacks are brief (few seconds to a maximum of two minutes), but typically occur repeatedly and periodically, can arise spontaneously or be triggered by innocuous stimuli, and are frequently accompanied by tic-like cramps of facial muscles. The condition affects women more often than men.


Trigonocephaly-bifid nose-acral anomalies syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by trigonobrachycephaly, facial dysmorphism (including narrow forehead, upward-slanting palpebral fissures, bulbous nose with slightly bifid tip, macrostomia with thin upper lip, micrognathia), and various acral anomalies, such as broad thumbs, large toes, bulbous fingertips with short nails, joint laxity of the hands and fifth finger clinodactyly. Short stature, hypotonia and severe psychomotor delay are also associated. There have been no further descriptions in the literature since 1991.


Trigonocephaly-broad thumbs syndrome is characterized by neonatal trigonocephaly and multiple anomalies including craniosynostosis, shallow orbits, unusual nose, deviation of the terminal phalanges of fingers 1, 2, and 5, and broad toes with duplication of the terminal phalanx. It has been described in a mother and her son. It is transmitted as an autosomal dominant trait.


Trigonocephaly-short stature-developmental delay syndrome

A rare developmental defect during embryogenesis characterized by premature closure of metopic sutures and/or other sutures, short stature, and developmental delay. Dysmorphic features include trigonocephaly, metopic ridge, narrow forehead, bitemporal narrowing, arched eyebrows, hypotelorism, deep-set eyes, epicanthal folds, strabismus, wide nasal bridge, small pointed nose, anteverted nostrils, long philtrum, low-set ears, malar flattening, narrow mouth, thin lips, high-arched palate, crowded teeth, and micrognathia. Variable additional manifestations may include conductive hearing loss, cerebral (mainly involving the white matter), skeletal (e.g. brachymesophalangy of the fifth fingers), cardiovascular and renal anomalies, inguinal hernia, hypospadias, and seizures.


TRIM22-related inflammatory bowel disease

A rare genetic gastroenterological disease characterized by infantile or childhood onset of severe gastrointestinal inflammation. Patients present with a variable phenotype including fever, diarrhea, failure to thrive, oral ulcers, fistulating perianal disease, strictures, granulomatous colitis, and recurrent bacterial and viral infections.


TRIM32-related limb-girdle muscular dystrophy R8

A mild subtype of autosomal recessive limb girdle muscular dystrophy characterized by slowly progressive proximal muscle weakness and wasting of the pelvic and shoulder girdles with onset that usually occurs during the second or third decade of life. Clinical presentation is variable and can include calf psuedohypertrophy, joint contractures, scapular winging, muscle cramping and/or facial and respiratory muscle involvement.


Triosephosphate isomerase (TPI) deficiency is a severe autosomal recessive inherited multisystem disorder of glycolytic metabolism characterized by hemolytic anemia and neurodegeneration.

Summary:
Epidemiology
Prevalence of TPI deficiency is unknown and less than 50 cases have been reported in the literature. The frequency of heterozygosity was estimated at 0.4-1% among Caucasians and Asians, and 4% among African Americans. These high values suggest that homozygosity is often lethal in utero. Frequent miscarriages in the affected families support this view.
Clinical description
TPI deficiency is a congenital disease. Hemolytic anemia occurs with very few exceptions and manifests with jaundice in most cases. Reticulocytosis and hyperbilirubinemia are common. Patients have often recurrent bacterial infections, most frequently affecting the respiratory system. In the classical generalized form of the disease, manifestations of progressive neurologic dysfunction become evident usually after 6-24 months of age, with dystonia, tremor, dyskinesia, pyramidal tract signs, cardiomyopathy and spinal motor neuron involvement with progressive neuromuscular impairment (severe weakness and muscle wasting). Cognitive function is not or mildly/moderately influenced and developmental retardation is more related to motor dysfunction affecting mobility (e.g. walking ability) and speech. Chronic axonal neuropathy was proved by nerve biopsy and peripheral electrophysiologic studies. In one case, severe convulsive microcephalic encephalopathy was also reported. Cerebrospinal fluid has been normal when studied, as have CT brain scans and EEG in two cases.
Etiology
TPI deficiency is due to mutations in the gene coding for the triosephosphate isomerase enzyme (TPI1, 12p13.31). The Glu104Asp substitution is the most frequent one, which accounts for approximately 80% of clinical TPI deficiency, and induces the most severe phenotype. However, many other mutations have been identified, mostly in compound heterozygotes coupled with the Glu104Asp mutation. These substitutions seems to result in a lack (Ile170Val, Phe240Leu) or delay (Cys41Tyr, Val231Met) of neurologic degeneration and an increased life expectancy.
Diagnostic methods
Diagnosis is based on physical examination and laboratory findings revealing enzymatic activity deficiency (2-30% of the normal values) and 15 to 100-fold accumulation of the toxic substrate dihydroxyacetone phosphate (DHAP) in erythrocytes. Muscle biopsy shows myopathic changes; nerve biopsy can be indicative for chronic axonal neuropathy. Molecular genetics can confirm diagnosis. Identification of genotype is crucial because of the different life expectancies.
Differential diagnosis
As an autosomal recessive inherited disease, TPI deficiency has a 25% recurrence risk in the case of heterozygous parents.
Antenatal diagnosis
Antenatal diagnosis is feasible in the first trimester by chorionic villus DNA analysis or by analysis of fetal red cells.
Management and treatment
There is no curative treatment for TPI deficiency. Management is based on repetitive red blood cell transfusions. Supportive care, if needed, consists of respiratory assistance. Neurological management is the same as in other progressive neuromuscular diseases.
Prognosis
Prognosis of TPI deficiency is poor, especially for patients homozygous for Glu104Asp mutation or heterozygous for a TPI null allele and Glu104Asp. In these cases life expectancy is generally reduced to infancy or early childhood, while patients carrying other mutations show longer survival. The most frequent cause of death is respiratory failure and infection. Central nervous system degeneration and cardiac failure were also reported as causes of death.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Pr Ferenc OROSZ


A rare genetic syndrome with limb duplication, polydactyly, syndactyly, and/or hyperphalangy characterized by duplication anomalies such as triphalangeal thumbs, phalangeal duplication of other digits, and polydactyly, associated with highly variable combinations of ectrodactyly, brachydactyly, and syndactyly of hands and/or feet. Severe nail dysplasia or absence of nails is also observed.


Triple A syndrome is a very rare multisystem disease characterized by adrenal insufficiency with isolated glucocorticoid deficiency, achalasia, alacrima, autonomic dysfunction and neurodegeneration.

Summary:
Epidemiology
Prevalence is unknown but less than 100 cases have been published since the first description in 1978.
Clinical description
The onset of Triple A syndrome varies between infancy and adulthood. When presenting in early childhood, alacrima and, possibly, achalasia are the indicative signs; in childhood and adolescence, onset is characterized by achalasia and adrenal insufficiency; while in adulthood, presentation is predominantly neurological with autonomous and polyneuropathic involvement. Alacrima, when present, is the first clinical sign, manifesting in the first months of life, but achalasia of the cardia, leading to dysphagia, is usually the first relevant symptom leading to diagnosis. Adrenal insufficiency may cause hypoglycemia and seizures. These three cardinal signs may not all be present, or be associated with autonomic dysfunction and other neurological features, leading to the ''double A'' or ''quaternary A'' denomination, respectively. Neurological manifestations are diverse: dysautonomia results in dyshidrosis and digestive, sexual, circulatory and urinary dysfunction; pyramidal syndrome and peripheral neuropathy lead to walking difficulties and sometimes to sensory deficit; and bulbar and facial deficiencies are responsible for velar insufficiency, tongue amyotrophy or paresis, orbicularis oris dysfunction and oropharyngeal dysphagia.
Etiology
The disease is caused by mutations in the AAAS gene (12q13), coding for the ALADIN nuclear pore scaffolding protein.
Diagnostic methods
Diagnosis is based on clinical examination and adrenal function testing. It can be confirmed by molecular testing.
Differential diagnosis
Given that the presence of 2 among the 3 main clinical signs (achalasia, alacrima or adrenal insufficiency) is pathognomonic, differential diagnosis can be considered when only one clinical sign is observed, for example at the onset of the disease. Differential diagnosis thus includes other causes of adrenal insufficiency, achalasia or alacrima such as frequent forms of congenital adrenal hyperplasia (easily excluded with dosage of adrenal hormones precursors), and rare peripheral forms of congenital adrenal insufficiency or adrenoleukodystrophy, which might be associated with neurological features.
Genetic counseling
Triple-A syndrome has an autosomal recessive mode of inheritance, thus causing a 25% recurrence risk for parents with an affected child.
Management and treatment
Treatment for Triple A syndrome includes hydrocortisone substitutive therapy, esophageal dilatation or myotomy of the lower esophageal sphincter and artificial tear drops. Management of neurological features is symptomatic.
Prognosis
If untreated, triple A syndrome may have a high morbidity and prognosis can be severe. The appropriate management of the disease ameliorates the prognosis significantly.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Pr Marc NICOLINO


Triploidy is a rare chromosomal anomaly, polyploidy, characterized by early in utero growth restriction, and multiple birth defects, including neural tube defects, facial abnormalities, cleft lip/palate, congenital heart anomalies, genital malformations, and peripheral skeletal abnormalities. It is usually prenatally lethal.


A rare, genetic, distal arthrogryposis characterized by pseudocamptodactyly, mild foot deformities, moderately short stature, and short muscles and tendons resulting in a limited range of motion of the hands, legs, and mouth, the later presenting with trismus.


Trisomy 10p is a syndrome of mental retardation/multiple congenital malformations (MR-MCA) that is caused by the total or partial duplication of the short arm of chromosome 10.

Summary:
Epidemiology
Around 50 cases have been described in the literature.
Clinical description
In complete trisomy 10p, the anomalies are present at birth. Children are usually dolichocephalic with a high and prominent forehead, contrasting with a small face, a distinctive implantation of hair that grows backwards, large sutures and a large anterior fontanelle, eyebrows that are fine, arched and that extend to the temples, a large nasal bridge that becomes prominent. The mouth is triangular, with not very apparent fleshy parts, the chin is round, often small and not well defined. The ears are large and low. A third of cases have a cleft lip and/or palate. Osteoarticular anomalies are frequent, including ligament hyperlaxity, flexion deformations of limbs, and club feet. Cardiac, renal (renal cystic dysplasia), ocular (coloboma, microphthalmia) and bone malformations have been reported. Hypochromic anemia is sometimes observed. Development is affected by severe intellectual and motor deficiency, and muscular hypotonia and hypotrophia.
Etiology
The majority of cases are a result of the malsegregation of a familial balanced translocation. The most frequent break point is located at the level of p11 band, but it can be more distal and result in partial trisomy. Other mechanisms can also be involved (pericentric inversion, duplication de novo, supernumerary chromosome...).
Diagnostic methods
The observation of a developmental anomaly associated with congenital anomalies leads to performing a karyotype which shows total or partial duplication of the short arm of chromosome 10, often associated with another imbalance. The identity of the chromosomal segment can be confirmed using in situ hybridization with probes specific to 10p. The parents' karyotype is essential in order to determine how the disease has occurred.
Differential diagnosis
Differential diagnoses include other syndromes of developmental delay with dysmorphism and congenital malformations.
Antenatal diagnosis
Prenatal diagnosis is possible, after the birth of the first affected child or after warning signs from an ultrasound, by choronic villus sampling (CVS) or amniocentesis in cases of structural anomalies in one of the parents.
Genetic counseling
In cases where the anomaly occurred de novo, the risk of recurrence in siblings is weak. When a structural anomaly is present in one of the parents, the risk will be evaluated depending on the type of anomaly.
Management and treatment
There is no specific treatment. Early multidisciplinary management and special education is necessary.
Prognosis
The prognosis is severe. A quarter to a third of patients die in the neonatal period. In other cases the progression is marked by severe intellectual and motor deficiency, and muscular hypotonia and hypotrophia. Partial trisomy with a break point at p13 result in similar characteristics but serious malformations are less frequent.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


A partial autosomal trisomy characterized by developmental delay and intellectual disability, generalized hypotonia, postnatal growth retardation, variable brain and heart anomalies and dysmorphic features, including frontal bossing, round face, full cheeks, low-set ears, broad nasal bridge, short nose with anteverted nares, long philtrum, thin upper lip vermilion, and everted, thick lower lip. Unspecific associated congenital anomalies have also been reported.


A rare chromosomal anomaly characterized by the presence of extra chromosome 13 material and manifesting with severe intellectual disability and multiple congenital anomalies including holoprosencephaly, microcephaly, microphthalmia, scalp defect, cleft lip/palate, congenital heart defects, and postaxial polydactyly. Neurological involvement may lead to seizures and hypotonia.

Summary:
Epidemiology
The incidence at birth is between 1/3500 and 1/5000. In 1st trimester diagnosis, the rate is 1/1,500 in the Danish register. Risk increases with maternal age.
Clinical description
In utero death occurs in over 95% of affected fetuses. Median survival is 7-10 days, and less than 30% survives beyond 1 year. Intrauterine growth retardation (IUGR) is common. Neurological manifestations are severe and present as hypotonia and hyporeactivity with an apparent lack of awareness of surroundings. Holoprosencephaly (resulting from a defect in the division of the brain into two hemispheres) is present in 70% of cases and can be observed as variable degrees of hemisphere fusion on MRI. Facial anomalies are variable and may range in severity from hypotelorism and premaxillary agenesis (80% of cases) to cyclopia. Cleft lip/palate (50-80%), micro- or anophthalmia (40%) eye coloboma, areas of cutaneous aplasia of the vertex (30%), postaxial polydactyly (50%), congenital heart defect (CHD) (80% of cases) and renal malformations (40%) may also be present.
Etiology
Free trisomy 13 (T13) is found in around 75% of cases. In 20% of cases, T13 is associated with a Robertsonian translocation in which the supernumerary chromosome 13 becomes attached to another acrocentric chromosome (chromosomes 13, 14, 15, 21 or 22). In rare cases, the syndrome is caused by reciprocal translocation between chromosome 13 and a non-acrocentric chromosome. Mosaic T13 (in which there is both trisomic and normal cell types) has been reported in a few patients with a clinical picture that varies between a normal phenotype and that of classical T13 according to the number of trisomic cells present in the tissues.
Diagnostic methods
T13 must be confirmed by conventional karyotyping. Chromosomal microarray will show T13 but may not discriminate free from translocation T13.
Differential diagnosis
The differential diagnosis includes trisomy 18, Smith-Lemli-Opitz syndrome, CHARGE Syndrome, Meckel syndrome and, in a minority of cases, other ciliopathies like Joubert syndrome and Bardet-Biedl syndrome (which may present with renal anomalies, polydactyly, brain anomalies).
Antenatal diagnosis
Analysis of fetal DNA in maternal blood (non-invasive prenatal testing; NIPT) has high sensitivity (> 97%). Maternal serum screening based on blood markers and nuchal translucency ultrasound scan may detect a proportion of T13 fetuses. Most T13 fetuses can be detected by routine fetal ultrasound scan (holoprosencephaly, polydactyly). Invasive prenatal testing like amniocentesis or chorionic villi sampling (CVS) will confirm any suspicion raised by prenatal screening.
Genetic counseling
The risk of recurrence of trisomy (21, 13 or 18) in families of an index case with T13 is around 1%. However, in families in which T13 is associated with translocation (Robertsonian or balanced) the risk of recurrence is higher if one of the parents is a carrier of a balanced translocation.
Management and treatment
Management is supportive/palliative only. Follow-up is needed for cardiac, respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic complications.
Prognosis
Surgical treatment of the malformations does little to improve the poor prognosis associated with this syndrome: half of the infants born alive die within the first month of life, 70% die before 1 year of age from cardiac, renal or neurologic complications, and 10% more die before 5 years of age. Prolonged survival (in some cases into adulthood) has been reported and is more common in cases of mosaic or partial trisomy and in the absence of severe brain malformations. In general, non-mosaic patients develop only limited autonomy (absence of speech and ambulation).

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Pr Alain VERLOES | ITHACA*

                                * European Reference Network


Trisomy 17p is a rare chromosomal abnormality resulting from the duplication of the short arm of chromosome 17 and characterized by pre- and post-natal growth retardation, developmental delay, hypotonia, digital abnormalities, congenital heart defects, and distinctive facial features.

Summary:
Epidemiology
It has been described in fewer than 15 patients.
Clinical description
Facial dysmorphism includes microcephaly, receding forehead, down-slanting palpebral fissures, ptosis, hypertelorism, low-set malformed ears, smooth philtrum, micrognathia, high-arched palate and a short broad neck. Digital abnormalities include absent fourth and fifth digits, brachydactyly and fifth finger clinodactyly. Genital hypoplasia in males and hypertrichosis are often observed. Intellectual deficit is severe to profound and the prognosis is poor.
Etiology
Trisomy 17p has been reported to be ``pure'', as the result of a de novo 17p duplication or an extra chromosome derived from the 17p arm. It can result from a recombination of a familial pericentric inversion, or from a malsegregation of a translocation, in which case trisomy 17p can be associated with monosomy of the partner chromosome.
Diagnostic methods
Diagnosis is based on standard and molecular karyotyping.

                            Last update:
                            May 2011

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


Trisomy 18 is a chromosomal abnormality associated with the presence of an extra chromosome 18 and characterized by growth delay, dolichocephaly, a characteristic facies, limb anomalies and visceral malformations.

Summary:
Epidemiology
Incidence is estimated at between 1/6000 and 1/8000 births. In utero death occurs in more than 95% of fetuses with this chromosome anomaly. For unknown reasons, the rate of survival is higher in females than in males, leading to a female predominance among live-born trisomy 18 infants.
Clinical description
Hypotonia, hyporeactivity and feeding problems (poor suction) are present in the first weeks of life and are followed by a progression to hypertonia with infants showing an apparent lack of awareness of their surroundings. Common features are intrauterine and postnatal growth delay, an emaciated appearance with hypotrophy, microcephaly with a narrow skull and dolichocephaly, microretrognathia, hypertelorism, and poorly modeled and angular ears. Foot anomalies include pes equinovarus and/or rocker-bottom feet and the fingers overlap (the fifth and second fingers with the fourth and third). Malformations are common with involvement of the eyes (microphthalmia, coloboma), heart (over 90% of cases) digestive tract (esophageal atresia, anorectal malformations), kidneys and urinary tract (hydronephrosis, uni- or bilateral agenesis). Less frequently, cleft/lip palate, arthrogryposis, radial aplasia, spina bifida and anencephaly, holoprosencephaly and omphalocele are observed.
Etiology
The majority of cases are associated with free trisomy 18. Mosaic trisomy 18 has been detected in a few patients presenting with a clinical picture that varies from classical trisomy 18 to a normal phenotype depending on the number of trisomic cells present in the tissues. The trisomy 18 phenotype appears to be associated with the presence of three copies of the 18q11-q12 interval.
Antenatal diagnosis
Trisomy 18 may be suspected during pregnancy from ultrasound findings (growth retardation, malformations, multiple choroid plexus cysts) and can be confirmed by karyotype analysis of the fetus. Serum markers (used for the diagnosis of trisomy 21) may also be abnormal.
Genetic counseling
The risk of recurrence of trisomy (21, 13 or 18) in families of an index case with trisomy 18 is around 1%. However, in families in which trisomy 18 is caused by translocation, the recurrence risk is higher if one of the parents is a carrier of a balanced translocation.
Management and treatment
Management is supportive only.
Prognosis
Surgical treatment of the malformations does little to improve the poor prognosis associated with this syndrome: 90% of infants die within the first year of life from cardiac, renal or neurological complications, or from repeated infections. Prolonged survival (in some cases into adulthood) has been reported, mainly in cases involving mosaic or partial trisomy (resulting from translocation). The majority of non-mosaic patients develop only limited autonomy (absence of speech and ambulation). The growth retardation is significant.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Pr Alain VERLOES


A rare partial trisomy of the short arm of chromosome 18 manifesting with a highly variable clinical phenotype which may include variable developmental delay and intellectual disability, epilepsy, and non-specific dysmorphic features, among others.


Trisomy 1q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 1, with a highly variable phenotype principally characterized by intellectual disability, short stature, craniofacial dysmorphism (incl. macro/microcephaly, prominent forehead, posteriorly rotated, low-set ears, abnormal palpebral fissures, microphthalmia, broad, flat nasal bridge, high-arched palate, micro/retrognathia), cardiac defects and urogenital anomalies. Patients may also present cerebral (e.g. ventriculomegaly) and gastrointestinal malformations, as well as dystonic tremor and recurrent respiratory tract infections.


Trisomy 20p is a chromosomal disorder resulting from duplication of all or part of the short arm of chromosome 20. It is mostly characterized by normal growth, mild to moderate intellectual disability, speech delay, poor coordination and evocative facial features.

Summary:
Epidemiology
Trisomy 20p is rarely reported. To date, fewer than 40 patients have been described.
Clinical description
Clinical manifestations linked to trisomy 20p comprise a variable degree of developmental delay and mild to moderate intellectual disability, poor motor coordination, marked speech delay with difficulties in the articulation of some sounds. Typical facial dysmorphisms include a round face with full cheeks, thick coarse and usually straight hair, laterally arched eyebrows, upward slanting palpebral fissures, flared nostrils, high arched palate, abnormal teeth, occipital flattening and large misshapen ears. Other common features include variable skeletal anomalies including vertebral malformations (fusion of vertebrae, reduction of intervertebral spaces, spina bifida, scoliosis and kyphosis), hip deformity, and malposition of fingers and toes. Osteoporosis/osteopenia is reported in a few patients. Congenital heart defects and non-specific kidney abnormalities are present in some patients. Birth weight and growth pattern are usually normal. Less frequent physical abnormalities include umbilical and/or inguinal hernias and hypospadias. The extent and severity of clinical manifestations described above is contingent on the size and location of the duplication in 20p.
Etiology
Trisomy 20p is a chromosomal abnormality resulting from duplication of a fraction of the short arm of chromosome 20, variable in length, with no recurrent breakpoints. It may occur de novo, but most reported cases arise from a reciprocal translocation or, as described in a few cases, a parental inversion. Trisomy 20p is therefore frequently associated with another chromosomal imbalance that may modify the clinical picture. Pure trisomy 20p resulting from isochromosome formation and whole arm translocation has been reported. Precise genotype-phenotype correlations remain elusive due to the small number of patients and heterogeneity of breakpoints.
Diagnostic methods
Diagnosis is based on clinical manifestations leading to chromosomal analysis. Depending on their size, partial 20p duplications may be diagnosed by classical or molecular karyotyping. Molecular techniques are necessary for the genetic characterization of the duplication (FISH, MLPA, CGH array).
Antenatal diagnosis
Prenatal diagnosis of 20p duplication is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Molecular techniques may be required depending on the size of the duplication.
Genetic counseling
Genetic counseling is recommended and requires parental karyotyping to evaluate their risk of having another affected child.
Management and treatment
Management is multi-disciplinary and requires evaluation and treatment by a pediatrician, and appropriate specialists. Patients will benefit from an early assessment and intervention with physiotherapy and occupational therapy.
Prognosis
The prognosis is variable, depending on the size and location of the duplication and on the quality and timing of treatment. Exact life expectancy is unknown, and depends on whether severe congenital anomalies are present. The majority of individuals with trisomy 20p will live into adulthood.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


Trisomy 4p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 4, with a highly variable phenotype, typically characterized by pre- and postnatal growth delay, psychomotor developmental delay and craniofacial dysmorphism (microcephaly, prominent glabelle, hypertelorism, enlarged ears with abnormal helix and antihelix, bulbous nose with flat or depressed nasal bridge, long philtrum, retrognathia with pointed chin). Additional features include skeletal (rocker bottom feet, arachnodactyly, camptodactyly) and renal malformations, cardiac defects, ocular abnormalities and abnormal genitalia in males.


Trisomy 5p is a chromosomal abnormality resulting from the duplication of a segment of variable size of the short arm of chromosome 5, which usually involves the distal band 5p15. The clinical presentation is variable but is always associated with severe intellectual deficit.

Summary:
Epidemiology
To date, more than 40 cases have been reported, the majority in association with another chromosomal anomaly.
Clinical description
Duplication of the 5p13 band determines the characteristic phenotype of trisomy 5p (the critical region): dolichocephaly or scaphocephaly with macrocephaly, oval elongated face, epicanthus, absent malar, long philtrum, ogival palate, macroglossia, dysplasic and low-set ears, micrognathia and short neck. Fingers are long. Patients may have microphthalmia or coloboma of the iris. At birth, the fontanelles are wide. Cerebral malformations (hydrocephalus, agenesis of the corpus callosum or Dandy-Walker malformation) are common. Visceral malformations are rare. Hypotonia is severe. There is a marked susceptibility to infections, especially respiratory infections, which can be life-threatening. Intellectual deficit is severe and may be accompanied by epilepsy. Larger duplications (up to the 5p11 band) have similar dysmorphisms, but more often are associated with failure to thrive, visceral and anorectal malformations, diaphragmatic hernia and club feet. Hydramnios may complicate pregnancy.
Etiology
The duplication may extend towards the centromere, to the 5p11 band. The majority of reported patients have a large duplication, visible on the standard karyotype. Small subtelomeric duplications are rare. Duplications that extend to the 5p14 band result in variable intellectual deficit, epilepsy and a specific phenotype. There are no established correlations between genes in the critical region and the phenotype observed. In the majority of patients the 5p duplication is associated with the deletion of another chromosome as part of a translocation (familial or de novo). ``Pure'' duplications are rare. Some patients have been reported with interstitial duplication of 5p or an extra chromosome derived from the 5p arm (possibly in the form of a 5p isochromosome); these patients have a phenotype comparable to classical duplication.
Diagnostic methods
Diagnosis is based on standard karyotyping or molecular determination of the karyotype (FISH, MLPA, CGH array).
Genetic counseling
In cases of de novo anomalies, the risk of recurrence is low and can be explained by the possibility of a mosaic germline parent.
Management and treatment
Disease management does not differ from that of other patients with severe intellectual deficit and includes physical and psychomotor therapy. Respiratory infections should be treated aggressively.
Prognosis
The prognosis is poor; many patients die in childhood as a result of neurological complications or respiratory infections.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Trisomy 8p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 8, with highly variable phenotype ranging from no dysmorphic features and only mild intellectual disability to patients with severe developmental delay, neonatal hypotonia, short stature, profound intellectual disability, mild dysmorphic features (e.g. mild ptosis, hypertelorism, down-slanting palpebral fissures, broad nasal bridge, short, prominent philtrum, abnormal dentition) and structural brain abnormalities. Autism, epilepsy, and spastic paraplegia have also been reported.


A partial autosomal trisomy characterized by developmental delay, intellectual disability, prenatal and postnatal growth retardation, congenital heart, genitourinary and skeletal anomalies, and dysmorphic facial features, including high and broad forehead, hypertelorism, upslanting palpebral fissures, broad nose, dysplastic and low set ears, micrognathia. Phenotypic features vary in relation to the duplication size.


Trisomy 9p is a rare chromosomal anomaly syndrome, resulting from a partial or complete trisomy of the short arm of chromosome 9, with a wide phenotypic variablility, typically characterized by intellectual disability, craniofacial dysmorphism (e.g. microcephaly, large anterior fontanel, hypertelorism, strabismus, downslanting palpebral fissures, malformed, low-set, protruding ears, bulbous nose, macrostomia, down-turned corners of mouth, micrognathia), digital anomalies (brachydactyly and clinodactyly), and short stature. Less frequently patients present with cardiopathy and renal, skeletal, and central nervous system malformations.


Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX).

Summary:
Epidemiology
It is the most common female chromosomal abnormality occurring in approximately 1 in 1,000 female births. However, as most individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed.
Clinical description
The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF; see this term) are also associated findings. Children with trisomy X have higher rates of motor and speech delays than in the general poplation, with an increased risk of cognitive deficits and learning disabilities presenting in the school-age years. Psychological problems such as attention deficits, mood disorders (including anxiety and depression), and adjustment disorders are also more common than in the general population.
Etiology
Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. Advanced maternal age (known to be associated with an increased likelihood of nondisjunction events) is noted in approximately 30% of trisomy X cases. Mosaicism (46,XX/47,XXX, 47,XXX/48,XXXX or in combinations including 45,X Turner's syndrome (see this term) cell lines) occurs in approximately 10% of cases. The phenotype in trisomy X is thought to be associated with overexpression of genes on the X-chromosome that escape X-inactivation but specific genotype-phenotype relationships remain to be defined.
Diagnostic methods
Diagnosis during the prenatal period by amniocentesis is common. Indications for postnatal diagnosis most commonly include developmental delay or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF.
Differential diagnosis
Differential diagnosis prior to definitive karyotype results includes fragile X syndrome, tetrasomy X, pentasomy X, and Turner syndrome mosaicism (see these terms).
Antenatal diagnosis
Patients diagnosed in the prenatal period should be followed closely for developmental delay so that early intervention therapies can be implemented as needed.
Genetic counseling
Genetic counseling is recommended, with families being informed about the sporadic nature of the chromosome anomaly, the wide variability in phenotype, and low risk of recurrence (< 1%-5%).
Management and treatment
Following diagnosis, clinical evaluation should be conducted to identify any manifesting features of the disorder. School-age children and adolescents often benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Fertility in women with trisomy X is generally considered normal, however, adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for hormonal abnormalities that may signal ovarian insufficiency. Patients should be referred to support organizations to receive individual and family support.
Prognosis
The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.

                            Last update:
                            June 2010

                            - Expert reviewer(s):
                            Dr Susan HOWELL  - Dr Ashley SUTHERLAND  - Dr Nicole TARTAGLIA  - Dr Callum WILSON  - Dr Rebecca WILSON  - Dr Lennie WILSON


A rare form of colour blindness characterized by a selective deficiency of blue vision.


Tropical endomyocardial fibrosis is a restrictive cardiopathy, occuring almost exclusively in children and young adults in tropical and subtropical regions, characterized by endocardial fibrosis, affecting the apices and the inflow tract of the right or left ventricle (or both) and manifesting with a restrictive cardimyopathy and atrioventricular regurgitation leading to severe pulmonary hypertension, very high systemic venous pressure and congestive cardiac failure. Suspected etiologies include helminth and protozoal infestation and malnutrition.


A rare pancreatic disease of juvenile onset occurring mainly in tropical developing countries and characterized by chronic non-alcoholic pancreatitis manifesting with abdominal pain, steatorrhea and fibrocalculous pancreatopathy. It is also commonly associated with the development of pancreatic calculi and pancreatic cancer at a much higher frequency than seen in ordinary chronic pancreatitis.


Tropical spastic paraparesis is a chronic systemic immune-mediated inflammatory myeloneuropathy, more frequently reported in women than in men, that usually presents in adulthood with slowly progressive spastic paraparesis of the lower limbs, bladder and bowel dysfunction, and sensory disturbances in the lower extremities (e.g. paresthesia and dysesthesia) and that is associated with a human T-cell lymphotropic virus type 1 (HTLV-1) infection.


A rare congenital limb malformation characterized by true congenital dislocation of the shoulder, developing in utero. It can be unilateral or bilateral and is usually associated with other abnormalities of the shoulder girdle, such as in the glenoid, the humeral head, the joint capsule, and the scapula. In addition, it may be accompanied by other malformations, like developmental hip dysplasia or cardiac malformation.


A rare, non-syndromic uterovaginal malformation characterized by a crescent-shaped, small-sized uterus containing a single horn and fallopian tube with no rudimentary horn. Urinary tract anomalies are frequently associated.


A rare, functioning, pituitary adenoma characterized by the presence of a pituitary mass associated with high levels of circulating, free, thyroid hormones in conjunction with normal to high levels of TSH and unresponsiveness of TSH levels to TRH stimulation and T3 suppression tests, typically manifesting with signs and symptoms of mild to moderate hyperthyroidism (e.g. goiter (most frequently observed), palpitation, excessive sweating, arrhythmia, weight loss, tremor) and/or tumor mass effect (such as headache, visual field defects, hypopituitarism). Occasionally, cosecretion of prolactin and/or growth hormone may cause galactorrhea and/or acromegaly.


Tuberculosis (TB) is a contagious-infectious disease caused mainly by Mycobacterium tuberculosis that in most individuals is usually asymptomatic but that in at risk individuals (e.g. with diabetes or with HIV infection) can cause weakness, fever, weight loss, night sweat, and respiratory anomalies such as chronic cough, chest pain, hemoptysis or respiratory insufficiency.


A rare neurocutaneous disorder characterized by multisystem hamartomas, most commonly involving the skin, brain, kidneys, lungs, eye, and heart, and associated with neuropsychiatric disorders.

Summary:
Epidemiology
Whilst prevalence has been historically estimated at 1/10,000, more recent data from the UK and Taiwan estimates prevalence at 1/20-25,000 and 1/100,000, respectively. However, current estimates are likely an underestimate given the variability in phenotypic expression, severity and age of onset.
Clinical description
Skin involvement is almost constantly present, beginning as hypomelanotic macules in the first years of life and evolving to facial angiofibromas by 3-4 years, followed by ungual fibromas, cephalic and lumbar (shagreen patch) fibrous plaques, and ''confetti'' skin lesions appearing in childhood to early adolescence. Brain involvement includes cortical dysplasias (tubers), subependymal nodules, and/or subependymal giant cell astrocytoma (SEGA), and is seen in almost all cases. SEGA affects 10 to 20% of tuberous sclerosis complex (TSC) patients, almost exclusively children and young adults. Early-onset epilepsy (focal seizures and/or infantile spasms) is present in 85% of patients. TSC-Associated Neuropsychiatric Disorders (TAND) include intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorders (ASD), psychiatric disorders, neuropsychological deficits, as well as school and occupational difficulties. Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria/retroperitoneal hemorrhage, abdominal masses, hypertension and renal failure. Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas appear during the fetal period, are rarely symptomatic, and tend to decrease in size in early childhood. Additional features include retinal and liver hamartomas, dental enamel pitting, intraoral fibromas, skeletal dysplasia, and rarely neuroendocrine tumors.
Etiology
TSC is due to mutations in either TSC1 (9q34) or TSC2 (16p13.3) which encode proteins that indirectly inhibit the mTOR pathway. In excess, mTOR causes increased cell growth and proliferation, as well as disproportionate glutamate activity leading to disrupted synaptic plasticity. Expressivity of TSC is variable due to mosaicism and to genetic-epigenetic modifiers.
Diagnostic methods
A definite diagnosis is defined as presence of ≥ 2 major features or 1 major and ≥ 2 minor features. Possible TSC is considered in the presence of 1 major or ≥ 2 minor features. The identification of a pathogenic variant, confirms the diagnosis regardless of the clinical findings.
Differential diagnosis
Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis is seen in up to 5% of patients presenting with TSC and should be excluded. Other differential diagnoses include vitiligo, Ito hypomelanosis, acne, skin rash, cardiac myxoma, isolated brain tumors, pulmonary emphysema, and kidney cysts.
Antenatal diagnosis
Antenatal diagnosis is made in two situations: familial cases with genetic diagnosis (amniocentesis, chorionic villus sampling) or de novo cases with the discovery of cardiac rhabdomyoma or less frequently brain abnormalities on routine pregnancy exams.
Genetic counseling
The disorder is autosomal dominant; however, two thirds of cases are the result of a de novo pathogenic variant. In one third of cases, TSC is inherited from one of the parents and, in such cases, genetic counseling is recommended to inform the parents that the risk of having an affected child is 50% for each pregnancy.
Management and treatment
Management is multidisciplinary and includes frequent clinical follow-up as well as treatment of epilepsy, tumors, and TAND. Early referral to a specialized pediatric epilepsy center is strongly recommended. Epilepsy treatment includes the use of vigabatrin (GABA transaminase inhibitor) for infantile spasms and early onset focal seizures. For pre-symptomatic infants, video electroencephalogram monitoring is recommended to identify subtle or electrographic seizures. If vigabatrin fails, other antiseizure medicine, ketogenic diet, vagal nerve stimulation, or mTOR pathway inhibitor (everolimus) might be helpful. Early identification of candidates for epilepsy surgery is highly recommended. The developing tumors require frequent follow-up and can be treated with mTOR inhibitors or surgery.
Prognosis
TSC is a chronic, life-long condition. As patients transition into adulthood, seizures may persist; renal and/or pulmonary issues may become more frequent and clinically significant.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Pr Alexis ARZIMANOGLOU | EpiCARE* - Pr Katarzyna KOTULSKA-JOZWIAK | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


A rare congenital myopathy characterized ultrastructurally by the presence of tubular aggregates in the subsarcolemmal region of the muscle fiber. It most commonly presents with slowly progressive proximal muscle weakness predominantly of the lower limbs, periodic paralysis, post-exertion muscle cramps, and muscular pain. Ocular anomalies like ophthalmoplegia or pupillary abnormalities may be associated. The intensity of the symptoms is variable, cases with normal muscle strength but myalgia or fatigue, as well as clinically asymptomatic cases have been described.


A rare, non-syndromic, congenital esophageal malformation characterized by a second structure with individual lumen and stratified squamous mucosa and muscularis mucosa lying within or adjacent to the true esophagus causing dysphagia, nausea, vomiting, retrosternal pain and respiratory problems (stridor and recurrent pneumonia) and usually presenting in childhood.


A rare genetic central nervous system malformation characterized by dysplasia of the superior cerebellum (especially the vermis), brainstem asymmetry, dysplasia of the basal ganglia, and cortical irregularities with asymmetric abnormalities in gyral size and orientation, as well as varying sulcal depth, but without lissencephaly, pachygyria, or polymicrogyria. Clinically, patients present global developmental delay with motor development usually being more affected that speech. Variable features are abnormal eye movements including oculomotor apraxia, strabismus, seizures, and behavioral problems.


Tubulocystic renal cell carcinoma is an extremely rare subtype of renal cell carcinoma most frequently characterized by a small, solitary, well-circumscribed, unencapsulated renal tumor composed of multiple small to medium-sized cysts with a white or gray, spongy ("bubble wrap-like") cut surface. Patients are usually asymptomatic or could manifest with abdominal pain, abdominal distension and/or hematuria. Progression, recurrence and metastasis rarely occur although lymph node, bone, pleura and liver metastases have been reported.


Tubulointerstitial nephritis and uveitis syndrome

A rare renal tubular disease characterized by early-onset tubulointerstitial nephritis associated with anterior uveitis.

Summary:
Epidemiology
Approximately 200 cases have been reported in the literature to date, although the disease is likely under-reported. It comprises up to a third of bilateral acute onset acute uveitis in patients younger than 20 years old. Females are predominantly affected with a female:male ratio of 2.5-5:1.
Clinical description
Presentation is typically in children and adolescents (median age of onset of 15 years old) with either uveitis (U) or tubulointerstitial nephritis (TIN). Symptoms of renal involvement are non-specific and can include polyuria/polydipsia, fever, general malaise, abdominal and flank pain, fatigue, arthralgia, myalgia or a non-specific rash. Ocular signs are eye pain and redness, loss of visual acuity and photophobia, though almost 60% of patients with confirmed uveitis present no symptoms. Uveitis is typically bilateral and anterior, but intermediate or posterior uveitis may occur. Of note, uveitis and TIN may occur synchronously or metachronously.
Etiology
The pathogenesis is unclear, but likely autoimmune in origin. The role of the cellular and humoral immunity is highlighted by studies demonstrating loss of T cell-tolerance and the presence in kidney and ocular tissue of antibodies against modified C-reactive protein. Certain HLA haplotypes are associated with a higher risk of the disease.
Diagnostic methods
There are no specific non-invasive tests to establish the diagnosis. Diagnosis should be suspected in patients with polyuria/polydipsia, rise in serum creatinine, elevated markers of tubular damage (such as low-molecular weight proteins), elevated urinary eosinophils, anemia and elevated erythrocyte sedimentation rate. A definitive diagnosis can be established by renal biopsy.
Differential diagnosis
Differential diagnoses should include secondary causes of tubulointerstitial nephritis and uveitis, such as infections (ex. TBC, viral infections as EBV or HIV, bacterial infections as chlamydia or mycoplasma; toxoplasmosis, brucellosis, histoplasmosis), granulomatous diseases as sarcoidosis, Sjögren syndrome, systemic lupus erythematosus (SLE), Wegener's granulomatosis and other as Behcet's disease, ankylosing spondylitis and inflammatory bowel diseases. The renal phenotype can be similar to nephronophthisis, which can also be associated with eye manifestations, albeit not in the form of uveitis.
Management and treatment
Treatment is typically with immunosuppression. Oral corticosteroids are the first line therapy and improvement in symptoms is typically seen within days to weeks of commencement. Use of other immunosuppressive therapies, such as cyclophosphamide, cyclosporine, methotrexate or mycophenolate mofetil has been reported. Topical corticosteroids are useful for TINU-associated uveitis. A careful ophthalmological follow-up is required to monitor possible long-term complications.
Prognosis
Prognosis is favorable as the disease resolves in most of patients. However, some cases progress to end-stage renal disease. There is a low risk of visual loss; however, ocular complications (such as posterior synechiae, cystoid macular edema, disc edema, elevated intraocular pressure and cataract) have been described in 20% of patients.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Detlef BÖCKENHAUER | ERKNet*

                                * European Reference Network


A rare vascular tumour that may be either congenital or acquired (appearing before the age of 5 years) with slow angiomatous proliferation.

Summary:
Epidemiology
The prevalence is unknown but around 200 cases have been described in the literature. However, not all cases of tufted angioma are published and a certain number of cases are probably misdiagnosed as noninvoluting congential haemangiomas (NICH).
Clinical description
Tufted angiomas appear as poorly delineated red plaques, sometimes containing scattered deep-red papules. In rare (usually congenital) cases, tumoural masses have been reported. The appearance of the lesions changes with time and they are sensitive upon palpitation, or even painful if subjected to trauma. The angiomas are sometimes covered by a layer of downy hair or encircled by a clear ring of tissue or halo.
Diagnostic methods
The diagnosis relies on the histological findings, which are characterised by a cannonball distribution of tufts of capillaries distributed throughout the dermis in a lobular arrangement. Lymphatic spaces and dermal fibrosis are frequently associated. Tufted angiomas are GLUT1-negative tumours that can be clearly distinguished from infantile haemangiomas.
Management and treatment
General corticotherapy, or therapy with alpha interferon or vincristine may be beneficial in severe cases with an extendedclinical course.
Prognosis
Although rare cases of spontaneous regression have been reported, the clinical course is often chronic. In some cases, tumours arising in the lower limbs infiltrate and progressively form a hardened (sclerous) tegument. This sclerosis may eventually reach the underlying muscle and joints, leading to significant functional problems. Tufted angiomas may be associated with Kasabach-Merritt syndrome (KMS), in which thrombopaenia can be life-threatening.

                            Last update:
                            May 2006

                            - Expert reviewer(s):
                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ


A rare bacterial infectious disease caused by Francisella tularensis and characterized by six major clinical presentations: ulceroglandular, glandular, oropharyngeal, oculoglandular, pneumonic, or typhoidal, depending on the route of infection. Early flu-like symptoms are common to all forms and are accompanied/followed by either a skin inoculation ulcer with localized lymphadenopathy; isolated lymphadenopathy; chronic pharyngitis with cervical lymphadenopathy; conjunctivitis with localized lymphadenopathy; lung involvement; severe systemic disease with neurological symptoms.


Tumor necrosis factor receptor 1 associated periodic syndrome (TRAPS) is a periodic fever syndrome, characterized by recurrent fever, arthralgia, myalgia and tender skin lesions lasting for 1 to 3 weeks, associated with skin, joint, ocular and serosal inflammation and complicated by secondary amyloidosis (see this term).

Summary:
Epidemiology
Annual incidence in Germany was estimated at 1/1,785,000 children under 16.
Clinical description
The onset of TRAPS is usually in infancy or childhood but rarely in adolescence or adulthood. TRAPS is characterized by recurrent episodes that begin with muscle cramps or migrating myalgia, followed by fever that typically lasts for 1 to 3 weeks along with skin, joint, abdominal and ocular manifestations. These episodes occur either spontaneously or after minor triggers (stress, infection, exercise etc). Skin manifestations include centrifugal, migratory, erysepela-like erythema, edematous plaques and urticarial lesions. Eye involvement can manifest in the form of conjunctivitis, periorbital edema (highly specific feature for TRAPS) or uveitis (see this term). Serosal inflammation (pleuritis, peritonitis) is common. Abdominal pain and arthralgias are frequent symptoms. Secondary amyloidosis with renal and hepatic manifestations may eventually develop. An increased risk of atherosclerosis and acute myocardial infarction has been noted.
Etiology
Mutations in the TNFRSF1A  (12p13.2) gene encoding TNFR1, that plays a key role in systemic inflammation, have been shown to underlie this condition. More than 70 mutations in the TNFRSF1A gene have been associated with TRAPS; about 50% of the mutations described (known as structural mutations) involve cysteine residues and are associated with a higher disease penetrance.
Diagnostic methods
During inflammatory episodes, laboratory tests reveal increased indicators of inflammation: raised erythrocyte sedimentation rate, C reactive protein, fibrinogen and haptoglobulin. There may also be an associated leucocytosis along with thrombocytosis, hypo or normochromic anemia and polyclonal hypergammaglobulinemia. The levels of serum amyloid A (SAA) protein and S100A12 correlate closely with disease activity and treatment efficacy. Serum level of soluble p55 TNF receptor (sTNFRSF1A) may be low. Urinary protein analysis helps to monitor evolution of renal amyloidosis. Mutational analyses can help confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes other diseases characterized by periodic fever such as familial cold urticaria, juvenile idiopathic arthritis, Behçet disease, PFAPA syndrome, and Muckle-Wells syndrome (see these terms).
Genetic counseling
The disease is transmitted in autosomal dominant manner with genetic heterogeneity and variable penetrance.
Management and treatment
Non steroidal anti-inflammatory agents are used for symptomatic relief. Inflammatory episodes can be controlled by corticosteroids but often increasing doses are required. Etenarcept, a TNF inhibitor has been shown to be effective. However its efficacy tends to wane during the time. IL-1 receptor agonist (anakinra) and monoclonal antibody to IL-1 (canakinumab) have also been used in treating TRAPS, providing an optimal control of the inflammatory manifestations in the long term.
Prognosis
With age, fever attacks may decrease in intensity and a more chronic and fluctuating course can be observed. Secondary amyloidosis complicates the course of the disease.

                            Last update:
                            September 2014

                            - Expert reviewer(s):
                            Dr Marco GATTORNO


Turcot syndrome with polyposis or Turcot syndrome type 2 is a form of familial adematous polyposis, characterized by the concurrence of thousands of colonic adenomatous polyposis or colorectal cancer (CRC) and a primary central nervous system tumor (principally medulloblastoma). It is also associated with pigmented ocular fundus lesions.


A rare chromosomal anomaly syndrome characterized by complete or partial loss of an X chromosome in phenotypic females, clinically manifesting with short stature, primary ovarian insufficiency as well as cardiovascular, renal, liver, autoimmune diseases, hearing loss and neurocognitive abnormalities.

Summary:
Epidemiology
Prevalence is about 5/10 000 live female births. Incidence among all conceptions is higher, since aneuploidy is a common cause of spontaneous abortion.
Clinical description
Patients typically present with significant statural growth retardation during childhood and/or primary ovarian insufficiency, often associated with homogeneous X monosomy. However, clinical features are heterogeneous and some may be milder or even absent in front of a 45,X/46,XX mosaic karyotype. Approximately 30% of patients will undergo the first pubertal stages such as breast development, 20% will experience spontaneous menarche and 95% have primary ovarian insufficiency before the age of 40. Around 5-7% are able to have a natural pregnancy. Patients may have a low posterior hairline, webbed neck, broad chest, hypoplastic nails, skeletal anomalies, congenital cardiovascular abnormalities (bicuspid aortic valves, aortic coarctation) as well as acquired vascular features, such as hypertension (50% of adult cases). Monitoring of aortic root diameters indexed to body surface area is recommended, since aortic bicuspidy, coarctation and hypertension may lead to aortic root dilatation and ultimately to aortic dissection. Other manifestations are renal defects, congenital lymphedema, liver steatosis or other hepatic diseases, ophthalmologic problems, hypothyroidism and autoimmune disorders. Intellectual disability is rarely reported, but patients may present impaired social skills and subtle cognitive difficulties. Variable comorbidities include obesity, insulin-resistance, conductive and sensorineural hearing impairment associated with repeated otitis media during childhood, and hyperlipidemia.
Etiology
X monosomy is the most common underlying etiology, while some cases have mosaicism or structural X chromosome anomalies. Clinical signs are more severe in patients with 45,X monosomy than in 45,X/46,XX or 45,X/46,XX/47,XXX mosaicism. Patients with an X isochromosome have a higher risk of liver and autoimmune diseases, while those with a ring chromosome are more prone to growth retardation and metabolic disorders. Haploinsufficiency of the SHOX gene is a well-established cause of short stature. The presence of Y material is related to the occurrence of gonadoblastoma.
Diagnostic methods
Suggestive clinical findings are confirmed by lymphocytic karyotype, demonstrating a 45,X cell line or deletion of the short arm (Xp) of the X chromosome. A second cell line study, such as buccal or urinary cell FISH analysis, may also be helpful.
Differential diagnosis
Differential diagnosis includes Noonan syndrome; 46,XX gonadal dysgenesis; 46,XY complete gonadal dysgenesis, SHOX-related short stature, as well as a single deletion of the long arm of the X chromosome downstream of Xq24.
Antenatal diagnosis
Typical forms with associated malformations can be diagnosed during ultrasound examination showing fetal abnormalities including diffuse edema, increased nuchal translucency, cystic hygroma, and left-sided obstructive cardiac anomalies. Noninvasive screening of circulating cell-free fetal DNA in maternal serum, amniocentesis or chorionic villus sampling can detect X chromosome abnormalities. Karyotyping must be repeated postnatally to confirm the diagnosis.
Management and treatment
Early diagnosis is beneficial, as it is recommended to start recombinant growth hormone therapy (GH) around 4-6 years and preferably before 12-13 years in case of growth failure (< 50th percentile) or short stature. This requires monitoring of insulin-like growth factor 1 and glycemia, due to a higher risk of glucose intolerance. A majority of patients require induction of puberty with estrogen replacement therapy at gradually increased doses, followed within 2 years by progestin supplementation to minimize endometrial hyperplasia and the long term risk of endometrial carcinoma. Hormonal replacement therapy with estrogen and progesterone/progestin is prescribed until the mean age of natural menopause (51 yrs). Lifelong follow-up is necessary, especially for the regular evaluation of aortic diameters.
Prognosis
Early diagnosis, timely pubertal induction, successful transition to adult care, and long-term follow-up by a multidisciplinary team are key elements in the achievement of optimal growth, psychosocial milestones and fertility.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Pr Jean-Claude CAREL | Endo-ERN* - Pr Sophie CHRISTIN-MAITRE | Endo-ERN* - Dr Bruno DONADILLE | Endo-ERN* - Pr Juliane LEGER | Endo-ERN*

                                * European Reference Network


Twin twin transfusion syndrome (TTTS) is a rare condition seen in twin monochorionic pregnancies, typically developing during the 15-26 week gestation period and usually due to unbalanced intertwin placental anastomoses, where an unequal exchange of blood between twins causes oligohydramnios in one sac and polyhydramnios in the other which can lead to a high perinatal mortality rate and a high rate of disability in survivors if left untreated


Typhoid or typhoid fever is a reportable, fecal-oral, potentially fatal infectious disease, caused by the bacteria Salmonella typhi and characterized by a non-focal fever.

Summary:
Epidemiology
The prevalence of typhoid is unknown but it is most commonly found in Asia, Africa and South America where access to properly treated drinking water may be limited. It is rare in Europe and Western countries and generally only occurs when imported from an endemic location. The annual incidence in Europe is estimated to be less than 1/30,000 persons/year.
Clinical description
Symptoms usually appear 1-7 days after ingestion of the bacteria and include high fever (39 to 40°C), chills, constipation or diarrhea, headache, stomach pain, malaise, rash of flat rose-colored spots on the chest and hepato-splenomegaly. Temperature rises for 2-3 days and remains elevated for another 10-14 days accompanied by bradycardia and prostration. In severe cases, delirium, stupor and coma can occur. In 1-2% of patients, intestinal lesions can lead to bleeding and death. Others may develop pneumonia in the second to third week. Intestinal hemorrhage and perforation (usually in the terminal ileum) is a serious complication that can occur 2-3 weeks after infection, and usually occurs in developing countries where treatment is not always available. The convalescence period may last several months. Patients can remain carriers after symptoms disappear. With treatment most patients recover after 5-7 days of therapy and death is extremely uncommon.
Etiology
Typhoid is caused by several serovars of Salmonella enterica, a Gram-negative bacterium, with S. typhi being the most common. It is transmitted by the fecal-oral route from human to human when food or water is contaminated with feces of infected individuals. There is no known zoonotic reservoir. Once ingested,  S. typhi multiply inside macrophages and spread throughout the body in the bloodstream where they travel to the bone marrow, liver and gallbladder and are shed in the bile and feces. Asymptomatic carriers can spread the disease as a consequence of gallbladder colonization.
Diagnostic methods
Diagnosis of typhoid is suspected in patients with fever who have recently travelled to an area where the disease is endemic. The only methodology currently able to categorically confirm a diagnosis of typhoid involves a microbiological culture of blood or bone marrow to detect S. typhi or other typhoidal organisms. The Widal test, an agglutination test, is used only in developing countries as it is rapid, inexpensive and does not require a specialized laboratory, but it lacks sensitivity and specificity.
Differential diagnosis
Other viral, bacterial or parasitic pathogens that cause diseases similar to typhoid include malaria, dengue fever, leptospirosis, typhus group rickettsia (see these terms), and influenza.
Management and treatment
Typhoid is treated with antimicrobials, typically fluoroquinolones, which are essential for bacterial clearance. Patients usually begin to recover after 2-3 days but must complete the course of treatment to prevent relapse or latent retention of the infection. If intestinal perforation occurs, surgical intervention is necessary immediately. When travelling to countries where typhoid is endemic, vaccinations are recommended. The two licensed vaccines currently available are the oral live attenuated vaccine Ty21a and the parenteral Vi polysaccharide vaccine. Travelers should take care to avoid unsafe drinking water and food prepared in unsanitary conditions. Any cases of typhoid should immediately be reported. Food should not be prepared by people who have been infected with typhoid recently as they may still be carriers.
Prognosis
Prognosis is good and complications rarely occur if treated quickly with antibiotics. In untreated cases the fatality rate can be as high as 20%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                             Stephen BAKER


Typical nemaline myopathy is a moderate neonatal form of nemaline myopathy (NM; see this term) characterized by facial and skeletal muscle weakness and mild respiratory involvement.

Summary:
Epidemiology
The annual incidence of NM has been estimated at 1/50,000 live births and the typical form to represent about 50% of all cases.
Clinical description
Disease onset is in the neonatal period. Patients have a long face, a high-arched palate and a tented upper lip. Skeletal anomalies may include kyphoscoliosis, pectus carinatum and pes cavus. In the first year of life, hypotonia and facial weakness are present and often contribute to failure to thrive and delayed motor development. Anti-gravity movements are present and respiratory muscle involvement is frequent. Nocturnal hypoxia and hypercarbia and lower respiratory tract infections are common manifestations. Joint hypermobility can be observed. In a minority of children weakness is more distal. Progression is very slow or absent and most patients are able to live an independent active life.
Etiology
Typical NM is caused by mutations of the ACTA1 (1q42.13), NEB (2q22) or TPM2 (9p13) genes, and disease transmission can be autosomal recessive or dominant.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


A rare inborn error of tyrosine catabolism characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone.

Summary:
Epidemiology
Birth incidence is 1/100,000 in most areas but is higher in some regions, notably in Québec, Canada.
Clinical description
The disease is clinically heterogenous. Symptoms may start during the first few months (acute type), in second half of the first year (subacute type) or in the following years up to adulthood (chronic type). In the acute type, manifestations of hepatic failure predominate (bleeding diathesis, hypoglycemia, ascites etc) with frequent sepsis and rapid deterioration. Mild proximal tubular disease is usually present. Subacute type manifests a similar but less severe clinical picture presenting usually with hepatomegaly or hypophosphatemic rickets (due to tubular dysfunction). Intercurrent illness may precipitate hepatic crisis. Chronic type presents with hepatomegaly secondary to cirrhosis and often tubulopathy, leading to rickets and renal failure. Neurological crises are infrequent presenting symptoms (in Europe but not in Canada); however, they can complicate any type of the disease when untreated. The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation. All patients stand a high risk of developing hepatocellular carcinoma (HCC).
Etiology
The deficiency of fumarylacetoacetate hydrolase, FAH(15q23-q25) results in accumulation of fumaryl-,maleyl-acetoacetate and their derivates, succinyl-acetone (SA) and succinyl-acetoacetate (SAA), that cause hepatorenal damage. SA leads to accumulation of delta-aminolevulinate (δ-ALA) resulting in inhibition of porphobilinogen synthesis and porphyria-like crises.
Diagnostic methods
Liver synthetic functions are usually severely affected with coagulopathy and hypoalbuminemia. Elevated levels of SA in dried blood spots, plasma or urine are pathognomonic. Other abnormalities include elevated α -fetoprotein, increased plasma levels of tyrosine, phenylalanine and methionine, increased urinary δ-ALA excretion and features of Fanconi tubulopathy. Confirmation of diagnosis is usually by mutation analysis. Newborn screening programs include testing for tyrosinemia type 1 (SA is the recommended marker).
Differential diagnosis
Differential metabolic diagnoses include classic galactosemia, hereditary fructose intolerance, and fructose 1,6 diphosphatase deficiency, Wilson's disease and some mitochondrial disorders.
Antenatal diagnosis
Antenatal diagnosis is possible with chorionic villus sampling and amniocentesis when a mutation has been identified in the family.
Genetic counseling
Tyrosinemia type 1 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
As soon as the diagnosis is confirmed (or even highly suspected) start nitisinone (NTBC) orally in a dose of 1-2 mg/kg a day along with the emergency treatment for acute liver failure if necessary. A protein-restricted diet must also be started in parallel. Patients should be referred to a specialist center for long term management. Liver transplantation should be considered in acutely ill infants (if liver function fails to respond to nitisinone within a week), suspected or diagnosed HCC, and non-compliance or unavailability of medical treatment.
Prognosis
Nitisinone treatment, combined with a low-protein diet allows most the patients to survive in good health. The prognosis is dominated by the risk of HCC, which increases the later the treatment is started.

                            Last update:
                            June 2023

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

                                * European Reference Network