A rare predominantly large-vessel vasculitis that is characterized by affected aorta and its major branches, but also other large vessels, causing stenosis, occlusion, or aneurysm.

Summary:
Epidemiology
Takayasu arteritis (TAK) prevalence has been estimated to be 13 to 40 per million habitants. Cases have been reported worldwide but TAK seems to be more frequent in asians. A high female-to-male sex ratio is well documented.
Clinical description
TAK generally presents before 40 years, although rare pediatric cases are found. Active periods of inflammation may present with non-specific features such as headache, malaise, palpitations, night sweats, polyarthralgia or arthritis, erythema nodosum-like or ulcerating nodular cutaneous lesions, fever, fatigue, and weight loss. Vascular manifestations depend on the location and extent of vessel involvement and occurrence of complications (vascular stenoses, occlusions, and more rarely aneurysms). Clinical features include claudication, rest pain (limbs), hypertension (renal), headache, blurred or double vision, optic atrophy, transient ischemic attack, stroke and seizures. Cardiovascular manifestations include bruit, murmurs, blood pressure difference of extremities, carotidodynia, congestive heart failure, aortic regurgitation or insufficiency, pulmonary hypertension and aortic or arterial aneurysm. Pulmonary artery involvement may result in pulmonary hypertension and coronary or bronchial-pulmonary shunts.
Etiology
The etiology of the inflammatory vasculitis in TAK is unknown. An underlying inflammatory mechanism and genetic factors are thought to play a role. Genetic studies have found HLA B-52 to be related to TAK. Recent GWAS studies revealed association of single nucleotide polymorphisms in IL12B and FCGR2A/3A genes to TAK.
Diagnostic methods
The diagnosis is difficult to establish and is frequently delayed (years or even decades). It is based on the clinical features and physical examination. Vascular manifestations could guide morphologic investigations. However, the main change is related to the use of noninvasive imaging techniques (ultrasound, magnetic resonance imaging, CT angiography and positon emission tomography). Such exams could allow early diagnosis by demonstrating arterial wall thickening or inflammation in the pre-stenotic phase.
Differential diagnosis
The differential diagnosis of TAK is very broad and may include other inflammatory diseases (atherosclerosis, giant cell arteritis, IgG4 related aortitis), infectious aortitis and fibromuscular dysplasia.
Management and treatment
Treatment and management depend on disease severity and the specific complications. Corticosteroid therapy is the main treatment modality for TAK although it is associated with known long-term adverse effects. Remission following immunosuppressive therapy is achieved in about 60% of cases. Other immunosuppressive agents may be needed to achieve relapse (methotrexate, azathioprine, mycophenolate mofetil, leflunomide, tacrolimus, or cyclophosphamide). Biologic drugs, first of all anti-TNF alpha and probably anti-IL6 could be used in patients resistant or intolerant to conventional treatment. Vascular interventions are used to re-establish vascular patency in stenosed and occluded arteries that cause organ ischemia or hypertension, and for aneurysmal disease.
Prognosis
TAK is associated with significant morbidity, especially when diagnosed late, and may be life-threatening in severe cases. Adverse effects from long-term corticosteroid therapy may reduce quality of life.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Pr Marc LAMBERT


A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by global developmental delay, intellectual disability, macrothrombocytopenia, lymphedema, and dysmorphic facial features (like synophrys, ptosis, eversion of the lateral portion of the lower eyelid, and thin upper lip, among others). Additional reported manifestations include cardiac and genitourinary anomalies, sensorineural hearing loss, ophthalmologic abnormalities, skeletal anomalies, and immunodeficiency. Brain imaging may show enlarged ventricles, cerebellar atrophy, or white matter changes.


A rare cardiac disease characterized by acute occurrence of heart failure after an emotional or physical trigger; recovery of the wall motion abnormalities are observed within months. Symptoms are similar to acute coronary syndrome (ACS).

Summary:
Epidemiology
Takotsubo syndrome (TTS) is found in about 1-3% of all patients with symptoms of ACS; however, the prevalence is likely underestimated. Around 90% of TTS patients are women, typically postmenopausal but male and younger patients are diagnosed increasingly due to raised awareness of the syndrome.
Clinical description
In the acute phase, clinical presentation, electrocardiography (ECG) and cardiac biomarkers are similar to those of ACS. Typical symptoms are acute chest pain or dyspnea. Further symptoms can arise from complications of TTS, e.g. heart failure, cardiogenic shock, or cardiac arrest. New ECG changes or elevated cardiac biomarkers may or may not be present.
Etiology
The underlying mechanisms of this syndrome remain incompletely understood. Recent findings show that specific alterations in neurological response and sympathetic activation after emotional stimuli are present in TTS. These findings confirm the importance of brain-heart interaction in the development of this process. Microcirculatory constriction is also proposed as an underlying mechanism.
Diagnostic methods
Diagnosis is often challenging due to the similarity with ACS. Coronary angiography with left ventriculography is considered the gold standard diagnostic tool. The InterTAK (international takotsubo) Diagnostic Criteria have been developed to improve diagnosis and include the following: 1) transient left ventricular dysfunction presenting as either apical, midventricular, basal or focal wall motion abnormalities with possible right ventricular involvement, 2) a preceding emotional, physical, or combined trigger (although not obligatory), 3) neurological disorders can be possible triggers, 4) presence of new ECG abnormalities (ST-segment elevation or depression, T-wave inversion, or QTc prolongation), 5) elevated cardiac markers (especially brain natriuretic peptide), 6) significant coronary artery disease can coexist, 7) absence of myocarditis.
Differential diagnosis
Differential diagnoses include AMI, myocarditis, spontaneous coronary artery dissection, or peripartum cardiomyopathy.
Management and treatment
Due to difficulty in distinguishing TTS from ACS, patients should be transferred to a chest pain unit upon presentation and receive guideline based treatment of ACS. There are no randomized clinical trials to support specific acute or long term treatment recommendations in TTS. However, the consensus statement from an international TTS expert panel provides recommendations for optimal treatment of TTS patients. Electrocardiogram monitoring is essential as a prolonged QT-interval may trigger malignant ventricular arrhythmias (torsades de pointes) or atrioventricular-block. Cardiogenic shock or post cardiac arrest requires intensive care with treatment according to the presence or absence of pulmonary edema, low left ventricular ejection fraction, hypotension and bradycardia. In all cases, inotropic substances should be avoided. For long term treatment, angiotensin converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are recommended as they are associated with improved survival and lower recurrence rates. Echocardiography should be performed during the acute phase to exclude right ventricular involvement, left ventricular outflow tract obstruction or intraventricular thrombus. A follow-up echocardiography should be performed after discharge to confirm recovery.
Prognosis
The spectrum of TTS is wide and ranges from low to very high risk. In-hospital mortality and long-term outcome in TTS are similar compared to ACS. Recovery of the left ventricular regional systolic dysfunction is usually observed after 4-8 weeks. The risk of recurrence is around 5%.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                             Victoria Lucia CAMMANN  - Pr Christian TEMPLIN  - Dr Jelena-Rima TEMPLIN-GHADRI


Tall stature-intellectual disability-renal anomalies syndrome

A rare overgrowth syndrome associated with multiple congenital anomalies characterized by tall stature, large hands and feet with large thumbs and halluces, spatulate digits, developmental delay and facial dysmorphism.

Summary:
Epidemiology
To date only 4 cases from 2 families have been reported in the literature.
Clinical description
The overgrowth disorder is characterized by tall stature, large hands and feet with large thumbs/halluces. Facial features include round face with widely spaced and deep-set eyes, epicanthal folds, flat midface, long and downslanting palpebral fissures, large prominent ears, thick lips, macroglossia. Patients exhibit developmental delay. Intellect ranges from normal with learning difficulties to intellectual disability. A range of variable congenital anomalies have been reported and include ocular defects (retinal coloboma or refraction errors), cardiac anomalies (ventricular septal defect, mitral valve prolapse, double chamber right ventricle), kidney malformations (renal malrotation with left bifid ureter, nephromegaly, cystic dysplastic kidneys), connective tissue disorders (inguinal hernia), as well as orthopedic features (talipes equinovarus, internal rotation of the femurs and tibias, bowing of the legs, and spina bifida occulta). Other features may include early-onset varicose veins, transient or chronic benign neutropenia (with normal bone marrow examination), sensorineural hearing loss, Wilms tumor (one patient) and early psychosis (one patient).
Etiology
Biallelic loss of function variants in FIBP (11q13.1) are responsible for this phenotype.
Diagnostic methods
Diagnosis is with next generation sequencing (exome, genome or panel for developmental disorders).
Differential diagnosis
Differential diagnosis includes other overgrowth disorders, such as Beckwith-Wiedeman syndrome or Simpson-Golabi-Behmel syndrome in the association with tall stature, nephromegaly, macroglossia, predisposition to Wilms tumor.
Antenatal diagnosis
Prenatal diagnosis can be proposed to parents with an affected child.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is multidisciplinary and depends on the particular manifestations and may include ophthalmological, cardiac, hematological and orthopedic evaluation and follow-up. Social care requirements for learning disability should be assessed. Psychiatric symptoms should be evaluated, in particular in adulthood. Hearing evaluations are required with possible prescription for hearing aids. Surgery may be recommended in cases of inguinal hernia and early-onset varicose veins. Follow-up for Wilms tumor with kidney ultrasound every 3 months from diagnosis to 8-years-old is recommended.
Prognosis
The possible lethality of the disorder has been questioned because of an increased occurrence of stillbirths and miscarriage in one family. A predisposition for Wilms tumor is suspected. Neutropenia does not seem associated with recurrent infections.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Laurence OLIVIER-FAIVRE | ITHACA*

                                * European Reference Network


Tall stature-long halluces-multiple extra-epiphyses syndrome

Tall stature-scoliosis-macrodactyly of the great toes syndrome is a rare, genetic, overgrowth or tall stature syndrome with skeletal involvement characterized by early and proportional overgrowth, osteopenia, lumbar scoliosis, arachnodactyly of the hands and feet, macrodactyly of the hallux, coxa valga with epiphyseal dysplasia of the femoral capital epiphyses and susceptibility to slipped capital femoral epiphysis.


Talo-patello-scaphoid osteolysis is an extremely rare form of primary osteolysis (see this term), described in two sisters to date, characterized by bilateral osteolysis of the tali, scaphoids, and patellae (accompanied by periarticular swelling and pain) and short fourth metacarpals (brachydactyly type E; see this term), in the absence of renal disease. Autosomal recessive inheritance has been suggested.


A rare, genetic neurometabolic disease characterized biochemically by an almost complete absence of plasma high-density lipoproteins (HDL), and clinically by liver, spleen, lymph node and tonsil enlargement along with multifocal peripheral neuropathy, corneal, skin and nail and, occasionally, cardiovascular disease.

Summary:
Epidemiology
Tangier disease (TD) prevalence is unknown. Approximately 200 cases have been described worldwide.
Clinical description
The clinical presentation and the severity of symptoms vary widely between patients. Although extremely low plasma HDL cholesterol may be detected fortuitously from birth, the most characteristic finding in children is large tonsils with a particular orange-yellow color due to carotene-enriched low-density lipoprotein (LDL) tissue-accumulation. Patients may also show asymptomatic hepatosplenomegaly, lymph node enlargement, corneal opacities and skin lesions with onset typically in childhood or adolescence. Multi-organ and tissue cholesterol deposition is also observed from biopsies (skin, bone marrow, nerves, muscles, and rectal mucosa). Anemia and thrombocytopenia may be present. Signs of atherosclerosis and cardiovascular disease are not observed before adulthood and when present, are associated with other major cardiovascular risk factors (e.g. high blood pressure or plasma triglycerides, diabetes mellitus, smoking, etc.). Isolated peripheral neuropathy is reported in over 50% of cases under two major phenotypes: a motor and sensory relapsing-remitting mono/polyneuropathy with onset during childhood or adolescence, and a syringomyelia-like syndrome with facial diplegia in adults with a past history of tonsillectomy in childhood. In some cases, patients may also show signs of corneal opacity and skin lesions such as skin ulcer, painless scalds or burn scars.
Etiology
The disease is due to mutations in the ABCA1 gene (9q31) encoding the ATP-binding cassette transporter (ABCA1), a cholesterol-efflux regulatory protein that is able to orient intra-cellular cholesterol and phospholipid trafficking towards the cell surface and to facilitate lipid transfer towards HDL and reverse cholesterol transport. Mutations thus result in very low levels of plasma HDL cholesterol and deposition of cholesteryl, retinyl esters, phospholipids and carotenoids in various non-adipose tissues.
Diagnostic methods
The diagnosis is based on evidence of an abnormal lipoprotein profile characterized by isolated hypoalphalipoproteinemia, extremely low HDL cholesterol (<5 mg/dL) and apolipoprotein A-I (ApoA1) levels (< 5 mg/dL), with only pre beta-1 HDL found by bidimensional electrophoresis in the plasma. Moderate hypertriglyceridemia, decreased LDL cholesterol levels, and occasionally, decreased total- and non-HDL plasma cholesterol are noted together with anemia, thrombocytopenia and mild inflammation. Skin, muscle or rectal mucosa biopsy reveals foam cells in affected tissues. Diagnosis is confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes familial Apolipoprotein A-I deficiency, LCAT deficiency and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, retinoids, paradoxical response to fibrates), liver failure or malignancies. When neuropathic manifestations are present, a plasma lipoprotein profile may rule-out TD diagnosis from other non-uniform demyelinating polyneuropathies, especially when prominent in the upper extremities.
Antenatal diagnosis
Prenatal diagnosis is feasible but is usually not performed.
Genetic counseling
Transmission is autosomal recessive, although relatives may exhibit lowered plasma HDLC while remaining asymptomatic.
Management and treatment
The disease has no specific treatment. Tonsillectomy may be required in case of significant tonsillar enlargement. A low-fat diet helps in reducing liver enlargement and preventing atherosclerosis. LDL-lowering drugs are required in patients with cardiovascular risk factors or overt signs of cardiovascular disease, especially when hepato-splenomegaly is absent. Therapies enhancing cellular cholesterol efflux by HDL are developed to reduce cardiovascular risk; anti-inflammatory agents and Miglustat (an iminosugar inhibitory of glycosyl-ceramide synthase) may correct neuropathic and skin manifestations despite being ineffective on plasma lipoprotein profile.
Prognosis
Prognosis is usually good and depends mainly on the progression of peripheral neuropathy. TD patients with extremely low plasma HDL cholesterol (<20 mg/dL) have increased risk of coronary artery disease in adulthood and should be offered regular cardiovascular and neurological monitoring.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Pascale BENLIAN


TARP syndrome is a rare developmental defect during embryogenesis syndrome characterized by Robin sequence (micrognathia, glossoptosis, and cleft palate), atrial septal defect, persistence of the left superior vena cava, and talipes equinovarus. The phenotype is variable, some patients present with further dysmorphic characteristics (e.g. hypertelorism, ear abnormalities) while others do not have any key findings. Additional features, such as syndactyly, polydactyly, or brain anomalies (e.g. cerebellar hypoplasia), have also been reported. The syndrome is almost invariably lethal with affected males either dying prenatally or living just a few months.


Tarsal kink syndrome is a rare congenital malformation of the tarsus that causes entropion characterized by blepharospasm and absence of an upper eyelid fold that may lead to corneal ulceration caused by the folded edge of the upper tarsus or the inturned eyelashes if not corrected by surgery.


Tarsal-carpal coalition syndrome is characterised by fusion of the carpals, tarsals, and phalanges.

Summary:
Epidemiology
Less than 10 affected families have been described so far.
Clinical description
At birth, patients present with stiffness of the proximal interphalangeal joint of the fifth digit, with or without bony synostosis. Proximo-distal progression leads to involvement of the fourth, third and then the second digits. Other anomalies include brachydactyly, humeroradial synostoses and, in some cases, short stature.
Etiology
Causative mutations in the NOG gene have recently been identified, showing that this syndrome is an allelic variant of symphalangism.
Differential diagnosis
Tarsal-carpal coalition syndrome can be distinguished from multiple synostoses syndrome and proximal symphalangism (see these terms) by the absence of hearing loss.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            September 2007


A rare multiple congenital anomalies syndrome characterized by tall stature due to postnatal overgrowth, mild to moderate intellectual disability, joint hypermobility and subtle distinctive facial features, which often become apparent during adolescence (such as round face, low-set, thick horizontal eyebrows, narrow palpebral fissures and prominent upper-central incisors). Overweight, hypotonia, behavioral and psychiatric problems are common. Other clinical features may involve seizures, cryptorchidism and cardiovascular diseases (including congenital heart disease and aortic root dilatation).


A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A deficiency as a consequence of biallelic pathogenic variants in the HEXA gene.

Summary:
Epidemiology
The prevalence of the disease is 1 case per 320 000 live births. It is more common in the Ashkenazi Jewish and French-Canadian populations.
Clinical description
Three forms have been described according to age of onset. The infantile form begins between 3 and 6 months of age for the early infantile (before 12 months) and between 12 and 24 months for the late infantile. The earliest signs are an incessant startle response to noise, and a progressive loss of vision. Psychomotor regression appears during the second semester of life with hypotonia, amaurosis, rapidly pharmaco-resistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present, strongly evocative even not specific. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. In the juvenile form, onset is between ages 2 and 10 with progressive cerebellar ataxia, leading to dystonia, behavioral disorders, loss of intellectual capacities, and a state of decerebration and death during the second decade. The late-onset form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Three initial clinical presentations are described: i) proximal lower limbs weakness with amyotrophy due to a motor neuropathy (mimicking progressive spinal amyotrophy; first complaint: difficulty to climb stairs) that eventually extends to upper limbs and distal parts of the limbs; ii) cerebellar ataxia; iii) more rarely psychotic symptoms with mood disorder. In the course of the disease the motor neuropathy almost always occurs, other motor symptoms may occur (dysarthria, swallowing disorder). Cognition is usually preserved.
Etiology
The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23).
Diagnostic methods
When Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement.
Differential diagnosis
GM2 gangliosidosis, AB variant, may perfectly mimic Tay-Sachs disease due to variants in GM2A gene which codes for a protein that activates hexosaminidase enzyme. In this disease, hexosaminidase A enzymatic activity is normal.
Antenatal diagnosis
Genetic prenatal and preimplantation testing is available.
Management and treatment
There is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.
Prognosis
For the pediatric form of Tay-Sachs, the severity is correlated to age of onset, with a more rapid regression in early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decades in the juvenile form. All patients will have pharmaco-resistant epilepsy in the advanced stages of the disease. For the adult form, the disease is usually very slow progressive and may last decades. Patients are progressively disabled, may lost the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Dr Nicole BAUMANN  - Dr Bénédicte HERON  - Dr Yann NADJAR | MetabERN* - Dr J TURPIN

                                * European Reference Network


TBCK-related intellectual disability syndrome is a rare, genetic, syndromic intellectual disability characterized by usually profound intellectual disability with absent speech, severe infantile hypotonia with decreased or absent reflexes, markedly slow motor development (with no progress beyond the ability to sit independently), early-onset epilepsy, strabismus and post-natal onset of progressive brain atrophy (incl. loss of brain volume, ex vacuo ventriculomegaly, dysgenesis of corpus callosum, white matter abnormalities ranging from non-specific changes to leukodystrophy). Swallowing difficulties, respiratory insufficiency, osteoporosis and variable craniofacial dysmorphisms (incl. plagio/brachicephaly, bitemporal narrowing, high-arched eyebrows, high nasal bridge, anteverted nares, high palate, tented upper lip) may constitute additional clinical features.


A rare, hereditary primary immunodeficiency characterized by recurrent respiratory tract infection, otitis media, candidiasis, diarrhea, as well as various signs and symptoms of immune dysregulation (hypereosinophilia, eczema, vitiligo, alopecia areata, autoimmune hemolytic anemia, pityriasis rubra pilaris). Failure to thrive, moderate lymphadenopathy and hepatomegaly have also been reported.


Teebi-Shaltout syndrome is a rare, genetic, development defect during embryogenesis malformation syndrome characterized by association of characteristic facial features (including abnormal head shape with narrow forehead, hypertelorism, telecanthus, small earlobes, broad nasal bridge and tip, underdeveloped ala nasi, small/wide mouth and high/cleft palate), ectodermal dysplasia (including oligodontia with delayed dentition, slow growing hair and reduced sweating) and skeletal abnormalities including camptodactyly and caudal appendage. Short stature and abnormal palmar creases are additional clinical features.


Tel Hashomer camptodactyly syndrome is a rare syndrome characterized by camptodactyly, muscle hypoplasia and weakness, skeletal anomalies, facial dysmorphism and abnormal dermatoglyphics.

Summary:
Epidemiology
Up to 2005, 20 cases had been reported.
Clinical description
Dysmorphic features include facial asymmetry, hypertelorism, broad nasal bridge, long philtrum and a small mouth. Winging scapulae, scoliosis, syndactyly and clinodactyly are commonly observed. The affected patients usually have normal mental development.
Etiology
The molecular basis of the syndrome has not yet been elucidated.
Genetic counseling
Inheritance is probably autosomal recessive.

                            Last update:
                            January 2011


Telecanthus-hypertelorism-strabismus-pes cavus syndrome is characterized by telecanthus, hypertelorism, strabismus, pes cavus and other variable anomalies. It has been described in a father and his son. The son also had hypospadias, bilateral inguinal hernia, clinodactyly and camptodactyly of the fingers, and radiographic findings including flared metaphyses of the long bones and osteopenia.


Telethonin-related limb-girdle muscular dystrophy R7

A mild subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a variable onset (ranging from infancy to adolescence) of progressive proximal upper and lower limb muscle weakness and atrophy. Mild scapular winging, calf hypertrophy, and lack of respiratory and cardiac involvement are also observed.


TELO2-related intellectual disability-neurodevelopmental disorder

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and intellectual disability, infantile hypotonia, microcephaly, movement disorder, and impaired balance. More variable manifestations are hearing loss, cortical visual impairment, abnormalities of fingers and/or toes, congenital cardiac anomalies, kyphoscoliosis, dysmorphic facial features, abnormal sleep pattern, and seizures, among others.


Temperature-sensitive oculocutaneous albinism type 1

An extremely rare form of oculocutaneous albinism type 1 characterized by temperature sensitive hair pigmentation leading to dark hair on the hands, feet, legs, arms and chest (cooler body areas) and white or pale yellow hair on the scalp, axilla and pubic area (warmer body areas). Nystagmus and reduced visual acuity are also noted.


TEMPI syndrome is a rare multi-systemic disease characterized by the presence of Telangiectasias, Erythrocytosis with elevated erythropoietin levels, Monoclonal gammopathy, Perinephric-fluid collections, and Intrapulmonary shunting.

Summary:
Epidemiology
Less than 10 cases have been described in the literature.
Clinical description
TEMPI syndrome manifests in mid-adulthood with the development of telangiectasias mostly on the face, trunk and arms, as well as with erythrocytosis which may cause a red facies and occasionally, headaches. The increased serum erythropoietin levels precede the intrapulmonary shunting. The intrapulmonary shunts cause hypoxia which slowly progresses until the person needs continuous supplemental oxygen. Blood clots, probably due to erythrocytosis, and bleeding in the brain have also been reported in some affected individuals. Monoclonal gammopathy and perinephric fluid collections are usually found incidentally and do not seem to cause any complications. The syndrome has a slow and regular progression.
Etiology
The cause of TEMPI syndrome is currently unknown. The abnormal plasma-cell clone and/or the monoclonal gammopathy are suggested to be triggers of the disease.
Management and treatment
Treatment has reportedly been completely or partially successful with the proteasome inhibitor bortezomib.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Pr Wilfried SCHROYENS


Temple syndrome due to maternal uniparental disomy of chromosome 14

A rare chromosomal anomaly characterized by prenatal and postnatal growth retardation, hypotonia, motor delay, early puberty, obesity, short adult stature, small hands and feet, mild intellectual disability, and mild dysmorphic facial features (frontal bossing, short nose with wide nasal tip, micrognathia, high palate, short philtrum).


A rare, genetic disease characterized by pre-and postnatal growth delay, feeding difficulties, muscular hypotonia, motor developmental delay (with or without mild intellectual disability) and mild facial dysmorphism, such as broad, prominent forehead, short nose with flat nasal root and wide tip, downturned corners of mouth, high-arched palate and micrognathia. Additonal features include childhood-onset central obesity, premature puberty and variable bone abnormalities (e.g. small hands and feet, dolichospondyly, slender long bones and craniofacial disproportion).


A rare, genetic, multiple congenital anomalies syndrome defined by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism.

Summary:
Epidemiology
To date, 9 cases have been reported in the literature.
Clinical description
Temple-Baraitser syndrome (TBS) is defined by the association of developmental delay (neonatal hypotonia, delayed developmental milestones), and intellectual disability which is most often severe. The characteristic finding is the presence of distal hypoplasia of digits (mostly the distal phalanges), which is more pronounced at, and often limited to, the thumbs and halluces; nail aplasia or hypoplasia is observed in all patients. In some patients, thumbs and halluces are broad or elongated, and pseudoepiphysis may be observed on X-ray imaging. Facial dysmorphism is characterized by a pseudo-myopathic appearance. Other reported facial features include high anterior or low frontal hairline with central cowlick, flat forehead, ptosis, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick helices, broad depressed nasal bridge with anteverted nares, short columella, long philtrum, high-arched palate, broad mouth with thick vermilion border of the upper or the lower lip and downturned corners. Seizures are reported in all patients, starting at a various ages. Poor visual contact and autistic behaviour are observed in most patients.
Etiology
TBS is due to heterozygous gain of function missense variants in the KCNH1 gene (1q32.2), lowering the activation threshold of the mutant voltage-gated potassium channel and delaying its deactivation. TBS is allelic to Zimmermann-Laband syndrome (ZLS), which differs from TBS by the presence of gingival fibromatosis, coarse facial features, hypertrychosis, hepato-splenomegaly, and more severe digital anomalies. As both syndromes have been described with the same variant, and some patients with KCNH1 variant but without full-blown TBS or ZLS have been reported, it is likely that TBS is part of a broader KCNH1-related disorder.
Diagnostic methods
Confirmation of clinical diagnosis is based on KCNH1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1.
Differential diagnosis
Differential diagnosis includes DOORS, Lynch Bushby and Zimmermann-Laband syndrome.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.
Genetic counseling
The disorder is autosomal dominant; however, most reported KCNH1 variants occur de novo. Mosaicism has been reported in two epileptic, but otherwise unaffected, mothers. Although not known, the recurrence risk to siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant.
Management and treatment
Management and treatment are based on the phenotype. Antiepileptic drugs, and physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated.
Prognosis
Prognosis depends on the severity of the phenotype.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Catheline VILAIN | ITHACA*

                                * European Reference Network


A rare, genetic, syndromic dysostosis characterized by bilateral, symmetrical, preaxial brachydactyly associated with hyperphalangy, motor developmental delay and intellectual disability, growth retardation, sensorineural hearing loss, dental abnormalities (incuding misalignment of teeth, talon cusps, microdontia), and facial dysmorphism that includes plagiocephaly, round face, hypertelorism, malar hypoplasia, malformed ears, microstomia and micro/retrognathia.


A very rare congenital genetic neurological disorder characterized by agenesis/hypoplasia of corpus callosum with developmental abnormalities, ocular disorders, and variable craniofacial and skeletal abnormalities.

Summary:
Epidemiology
The syndrome is rare and has been reported in more than 7 families to date, representing 56 affected individuals. While generally considered a rare disease, one large cohort of Arab patients (1000 individuals) suggested that start codon mutations in C12ORF57 alone accounts for 1.5% of all cases of intellectual disability, a contribution that rivals that of the much more familiar Fragile‐X syndrome and would make it the single most common cause of recessive intellectual disability/developmental delay in Saudi Arabia. Most affected families are of Middle-Eastern Arab descent, specifically Saudi Arabian. Most reported families have multiplex cases of Temtamy syndrome and almost all are from consanguineous unions. Male and female patients have been reported.
Clinical description
Age of onset is generally in the neonatal period and in infancy. The manifestations of Temtamy syndrome are variable. The main clinical findings are dysmorphic facies (including elongated face, hypertelorism, prominent nose, low-set ears, and micrognathia), hypotonia, moderate to severe intellectual disability, intractable seizures and autistic features such as absent language or stereotypy. Motor and cognitive delay usually manifests in early childhood. Skeletal anomalies may include brachydactyly of the hands and feet, genu vara, and pes planus. Visual abnormalities include microphthalmia, coloboma of iris, esotropia, and optic atrophy, sometimes leading to progressive loss of vision. Atrial septal defect was also found in some patients. Involvement of other systems was not reported.
Etiology
The pathogenesis of Temtamy syndrome is not known. Various mutations (homozygous, missense, compound heterozygous) in the C12ORF57 gene (12p13.31) have been reported in affected patients. The gene is of unknown function but appears to be required for development of the corpus callosum and the eye. It is expressed primarily in the neurological, visual, and cardiovascular systems. In vitro cellular expression studies indicated that the mutation decreased protein synthesis suggesting the lost-of-function mechanism and phenotypic variability.
Diagnostic methods
Diagnosis is based on the specific constellation of clinical signs and brain imaging. Brain magnetic resonance imaging (MRI) of affected patients has shown aplasia, thickening, or hypoplasia of the corpus callosum, thalamic hypoplasia, and rarely colpocephaly.
Differential diagnosis
Differential diagnoses include muscle-eye-brain disease, Peters-plus, Walker-Warburg, Aicardi, Donnai-Barrow, and Baraitser-Winter syndromes.
Genetic counseling
Temtamy syndrome follows an autosomal recessive pattern of inheritance. Genetic counseling should be offered to affected families.
Management and treatment
Currently, management of the disease is symptomatic.
Prognosis
Prognosis and quality of life depend on the severity of disease manifestations.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Elliott SHERR


A rare benign proliferative disorder of the synovial membrane primarily affecting young adults (with a peak age of onset in the second to fourth decade of life) characterized by proliferative, locally invasive tumor-like lesions, usually involving a single joint, tendon sheath or bursa (most commonly the joints of the knee and hip and rarely others such as the ankle, shoulder and temporomandibular joints). It presents with pain and limitation of motion along with swelling, heat and tenderness over the involved joint, eventually leading to arthritic degeneration and significant locomotor deficit, if left untreated. PVNS can recur in patients even after treatment.


Terminal osseous dysplasia-pigmentary defects syndrome is characterised by malformation of the hands and feet, pigmentary skin lesions on the face and scalp and digital fibromatosis.

Summary:
Epidemiology
It has been described in 18 females, six of whom came from four different generations of the same family.
Clinical description
Phenotypic expression is very heterogeneous. In the majority of patients, the bone dysplasia is limited to the hands and feet but shortening and/or bowing of the bones of the arms and legs has been reported in severe cases. The pigmentary lesions and digital fibromatosis appear a few months after birth.
Etiology
The causative gene remains unknown.
Genetic counseling
The syndrome is transmitted as an in utero male-lethal X-linked dominant trait, explaining the large number of miscarriages reported in the affected families.

                            Last update:
                            September 2007


A rare disorder of the anterior segment of the eye characterized by slowly progressive, bilateral, asymmetric, usually non-inflammatory degeneration of the peripheral cornea, resulting in stromal thinning, vascularization, lipid deposition, and against-the-rule astigmatism with decreased visual acuity. Degeneration typically involves the superior aspect of the cornea first and extends circumferentially, leading to circumferential ectasia of the peripheral cornea. Opacification of the central cornea may occur at a very advanced stage. In rare cases, the condition is complicated by perforation.


A rare oblique facial cleft characterized by a congenital unilateral or bilateral oculo-facial defect beginning at the upper lip lateral to the Cupid's bow, then running lateral to the nasal wing, to the lower eyelid lateral to the inferior punctum. Involvement of the facial skeleton begins between the lateral incisors and the canine tooth, involving the maxillary sinus, and ending at the infraorbital rim. Variable involvement of the eye can result in micro- or even anophthalmus.


A rare oblique facial cleft characterized by a congenital unilateral or bilateral defect beginning in the upper lip medial to the oral commissure and extending across the cheek as a groove ending between the middle and lateral third of the lower eyelid (resulting in coloboma). Bone involvement includes an alveolar cleft in the premolar region, extending across the maxilla lateral to the infraorbital nerve and up to the infraorbital rim and orbital floor. The malformation may be associated with Tessier number 3 and number 4 clefts, macrostomia, or anophthalmos.


A rare oblique facial cleft characterized by a defect between the maxilla and the zygomatic bone, opening into the infra-orbital fissure, accompanied by coloboma of the lower eyelid and a vertical furrow on the cheek oriented either laterally to the corner of the mouth or in the direction of the angle of the mandible. The posterior aspect of the maxilla is short with a high palate and choanal atresia. The malformation is typically associated with Treacher-Collins syndrome.


A rare lateral facial cleft characterized by a temporo-zygomatic defect, usually with absence of the zygomatic arch and deformities of the mandibular ramus, condyle, and coronoid process. Associated soft tissue abnormalities include malformations of the ear and hypoplasia or absence of the temporal muscle. Preauricular hair may be absent or divided into two portions. Facial manifestations include macrostomia (with extension of the cleft to the corner of the mouth) and pre-auricular tags. Incomplete clefts may be found in the molar region and between the maxillary tuberosity and pterygoid process.


A rare 46,XY disorder of gonadal development characterized by congenital complete absence of testicular tissue in an individual with an otherwise normal male phenotype and normal karyotype. In addition, a small penis is a frequent finding in anorchid patients. Typical hormonal characteristics are elevated basal levels of gonadotropins (especially FSH), low concentration of testosterone, and lack of increase of plasma testosterone in response to hCG administration. The GnRH stimulation test induces a prolonged increase in FSH and LH levels.


Testicular regression syndrome (TRS) is a developmental anomaly characterized by the absence of one or both testicles with partial or complete absence of testicular tissue. TRS may vary from normal male with unilateral no-palpable testis through phenotypic male with micropenis, to phenotypic female. The phenotype depends on the extent and timing of the intrauterine accident in relation to sexual development.


Testicular seminomatous germ cell tumor is a rare testicular germ cell tumor (see this term), most commonly presenting with a painless mass in the scrotum, with a very high cure rate if caught in the early stages.

Summary:
Epidemiology
Annual incidence in Europe is 1/62,000 people. It accounts for 40% of testicular cancer cases.
Clinical description
Seminoma usually presents in males between the ages of 30-40. A painless mass in the scrotum is indicative of disease. A long-standing hydrocele may be noted causing a feeling of heaviness in the testicle. Gynecomastia and back and flank pain are symptoms that are seen in some patients. Relapse after surgery can occur, usually (in 97% of cases) in the high iliac or retroperitoneal lymph nodes. Metastasis, although rare, can occur in some cases, affecting the lungs, liver, bones and central nervous system.
Etiology
Etiology is unknown but tumors are thought to arise from an embryonic germ cell leading to testicular intraepithelial neoplasia (the precursor to classical seminoma). Cryptorchidism is a risk factor for the development of testicular seminomatous germ cell tumors.
Diagnostic methods
Ultrasound usually confirms the presence of a testicular mass. Measurement of tumor markers in blood such as alpha-fetoprotein (AFP), beta human chorionic gonadotropin (BHC) and lactate dehydrogenase (LDH) is needed as it can be useful in cases where the tumor is still very small. Classical seminoma does not secrete AFP and patients with raised levels of this tumor marker are given a diagnosis of non-seminoma. After surgical removal of testicle, histopathological characteristics are analyzed and a stage can be assigned. In stage 1 disease the primary tumor is limited to the testis and epididymus with possible invasion of the tunica albuginea, tunica vaginalis, spermatic cord and scrotum but no lymph node or distant metastasis. Stage 2 (2A, 2B and 2C) disease features regional lymph node metastasis and stage 3 has distant metastasis of varying degrees.
Differential diagnosis
Testicular non seminomatous germ cell tumors (see this term) must be excluded.
Management and treatment
Treatment for stage 1 seminoma involves an orchiectomy or partial orchiectomy in some cases. Most patients (88%) do not require any further treatment and only surveillance is necessary. In those cases where follow up is difficult, adjuvant carboplatin or radiotherapy can be applied. Para-aortic and ipsilateral iliac radiotherapy (30 Gy in 2 Gy fractions) is the standard treatment of stage 2A seminoma. Cisplatin, etoposide and bleomycin (PEB) chemotherapy (three cycles) or cisplatin and etoposide (PE) chemotherapy (4 cycles) is an alternative to radiotherapy (but has more acute toxicity). Those with stage 2B, 2C and stage 3 seminomas are given PEB chemotherapy (three or four cycles depending on prognosis). In those with a reduced lung capacity or with emphysema or in severe smokers, 4 cycles of PE is preferred over PEB. Ifosfamide is given instead of bleomycin in certain cases (i.e. patients with existing lung damage). Follow up and sometimes a PET scan is recommended to monitor for residual lesions. Due to cosmetic and psychological reasons, patients may be offered testicular prostheses after an orchidectomy.
Prognosis
Prognosis is good but depends on the stage of disease with 5- year survival rates as high as 99% in stage 1 disease. Relapse rates at 5 years depend on risk factors (ex. invasion of the rete testis, tumor size >4cm) present, but is only 12% in those with no risk factors.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Hans-Joachim SCHMOLL


A rare neoplastic disease characterized by the presence of a testicular tumor composed of several, well-differentiated or immature, tissues derived from one or more of the 3 germinal layers. Patients typically present unilateral (occasionally bilateral) painless testicular swelling or a palpable testicular nodule/mass.


A toxin-mediated infection due to the anaerobic bacteria Clostridium tetani and characterized by spasms and contractions of the skeletal muscles, the disease is often lethal.

Summary:
Epidemiology
Tetanus has almost disappeared from countries where a vaccination policy is ensured and implemented. Annual incidence in developed countries is less than 1 / 1,000,000 inhabitants, and mainly affects patients over 70 years of age. The annual incidence is 100 to 200 times higher in the poorest countries. There are no international statistics on the number of adult cases. In 2015, the number of newborn deaths recorded was 34,000. In 2018 neonatal and maternal tetanus was eliminated in 14 of the 57 countries deemed to be at high risk.
Clinical description
Tetanus can occur at all ages. The first symptoms appear 4 to 20 days after a wound contamination and begin by a trismus. In a few hours or a few days (depending on the severity), these painful contractures will spread to the whole body; they can be accompanied by dysautonomics disorders. Death can occur from respiratory blockade.
Etiology
Tetanus caused by Clostridium Tetani, a bacterium found in almost all soils and animal droppings and present as spores. It enters the body through a contaminated wound, and produces a neurotropic toxin which gains, following the nervous axes, the neuromuscular junctions where it attaches, causing spasms and contractures of the striated muscles.
Diagnostic methods
Diagnosis is exclusively based on clinical signs.
Differential diagnosis
Differential diagnosis includes local causes of trismus, muscular dystonia induced by certain drugs, and much more rarely, meningitis or certain forms of hysteria.
Management and treatment
Treatment is symptomatic and aims to control contractures with large doses of muscle relaxant drugs or even prolonged curarization, until the toxin is removed, which often requires respiratory resuscitation. The only effective treatment is vaccination. It is 100% effective and there are almost no contraindications. In practice, a vaccine recipient (three injections and a booster after one year, followed by the scheduled booster) will never get tetanus. For injured individuals whose vaccination status is uncertain, the risk of tetanus is constant, and the systematic administration of specific gamma globulin necessary.
Prognosis
The prognosis is variable. The disease lasts from 2 to 4 weeks, the mortality varying between 20 and 80% depending on the severity of the disease, the age of the patient and the local possibilities of resuscitation.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr François TREMOLIERES


An extremely rare mostly lethal congenital disorder characterized by absence of all four limbs and frequent associated major malformations involving the head, face, eyes, skeleton, heart, lungs, anus, urogenital, and central nervous systems. The syndrome has been described in fewer than 20 patients mainly of middle Eastern descent.


A rare, sex chromosome disorder of sex development characterized by the two different haploid sets of maternal and paternal chromosomes and variable phenotype - from normal male or female genitalia, to different degrees of ambiguous genitalia, and often infertility. Also, in the cases of monochorionic dizygotic twins, it can be confined to blood of both twins.


A form of phenylketonuria (PKU), an inborn error of amino acid metabolism, characterized by mild to moderate symptoms of PKU including impaired cognitive function, seizures, and behavioral and developmental disorders, and a marked reduction of elevated phenylalanine concentrations after oral loading with tetrahydrobiopterin (BH4), an essential cofactor of phenylalanine hydroxylase.


Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy.

Summary:
Epidemiology
This combination of lesions occurs in 1 of every 35,0000-30,000 live births, and accounts for 7-10% of all congenital cardiac malformations.
Clinical description
Patients nowadays usually present as neonates, with cyanosis of varying intensity based on the degree of obstruction to flow of blood to the lungs.
Etiology
The aetiology is multifactorial, but reported associations include untreated maternal diabetes, phenylketonuria, and intake of retinoic acid. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. The risk of recurrence in families is 3%.
Diagnostic methods
Useful diagnostic tests are the chest radiograph, electrocardiogram, and echocardiogram. The echocardiogram establishes the definitive diagnosis, and usually provides sufficient information for planning of treatment, which is surgical.
Differential diagnosis
Differential diagnosis includes primary pulmonary causes of cyanosis, along with other cyanotic heart lesions, such as critical pulmonary stenosis and transposed arterial trunks (see these terms).
Antenatal diagnosis
Approximately half of patients are now diagnosed antenatally.
Management and treatment
Neonates who present with ductal-dependent flow to the lungs will receive prostaglandins to maintain ductal patency until surgical intervention is performed. Initial intervention may be palliative, such as surgical creation of a systemic-to-pulmonary arterial shunt, but the trend in centres of excellence is increasingly towards neonatal complete repair. Centres that undertake neonatal palliation will perform the complete repair at the age of 4 to 6 months.
Prognosis
Follow-up in patients born 30 years ago shows a rate of survival greater than 85%. Chronic issues thatnow face such adults include pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. As the strategies for surgical and medical management have progressed, the morbidity and mortality of those born with tetralogy of Fallot in the current era is expected to be significantly improved.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Robert ANDERSON  - Dr Fédérique BAILLIARD


Tetramelic monodactyly is a rare, genetic, congenital limb malformation disorder characterized by the presence of a single digit on all four extremities. Malformation is typically isolated however, aplastic and hypoplastic defects in the remaining skeletal parts of hands and feet have been reported. There have been no further descriptions in the literature since 1992.


Tetraploidy is an extremely rare chromosomal anomaly, polyploidy, when an affected individual has four copies of each chromosome, instead of two, resulting in total of 92 chromosomes in each cell. The phenotype is severe with multiple congenital anomalies, including central nervous system, ocular, cardiac, renal, and/or genital malformations and limb defects. Most patients show severe intrauterine growth retardation, hypotonia, failure to thrive and developmental delay. It is usually associated with miscarriage.


Pallister-Killian syndrome (PKS) is a rare multiple congenital anomaly/intellectual deficit syndrome caused by mosaic tissue-limited tetrasomy for chromosome 12p.

Summary:
Epidemiology
Incidence is uncertain and is estimated around 1/25,000.
Clinical description
A number of cases are prenatally diagnosed because of abnormal ultrasonic findings, and abnormal presentation at birth is usual. Most common signs include facial dysmorphism, rhizomelic limb shortness, small hands and feet with nail hypoplasia. Craniofacial manifestations include a ``coarse'' face with flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, upslanting palpebral fissures, hypertelorism, flat and broad nasal bridge, short nose with upturned nares, large mouth with downturned corners and prominent upper lip. Macroglossia and pointed chin occur with age. Hypotonia is present at birth with contractures developing with age. A wide range of congenital malformations may be present, the most specific being diaphragmatic and anal defects. Heart defects, mainly ventricular septal defects, are present in 25% of cases. Severe intellectual deficit, pigmentary skin anomalies, deafness and seizures are frequent signs.
Etiology
Patients with PKS have mosaïcism for a supernumerary isochromosome 12p, resulting in four copies of the short arm of chromosome 12 instead of the normal two. The isochromosome is mostly of maternal origin. Selection against i(12p) cells is observed in vitro, and probably also occur in vivo. Karyotype is 47, XX or XY, i(12)(p10)/ 46,XX or XY.
Diagnostic methods
Clinical recognition is very important as the additional chromosome is usually absent from routine blood lymphocytes examination. Cytogenetic diagnosis requires skin biopsy and fibroblast chromosome examination. The isochromosome is usually present in 30-100% of fibroblast metaphases. In situ hybridization with chromosome 12-specific DNA probes can be used to confirm the chromosome identity. Interphase FISH on a buccal smear may allow a fast preliminary diagnosis.
Differential diagnosis
Differential diagnoses include trisomy 12p and Fryns syndrome (see these terms). Antenatal diagnosis may be possible through ultrasound examination revealing abnormal findings such as diaphragmatic hernia, polyhydramnios, hydrops fetalis, cardiac malformations, short limbs, and other, leading to amniocentesis and chromosomal diagnosis.
Antenatal diagnosis
Antenatal diagnosis is also possible after choriocentesis for maternal age.
Genetic counseling
All reported cases of this disorder have been sporadic.
Management and treatment
There is no specific therapy. Affected children may benefit from early intervention programs and special education.
Prognosis
Prognosis is usually poor. Death may occur perinatally, mainly due to diaphragmatic hernias, or during the first years of life in about a half of patients. Intellectual deficit is mostly profound and almost always accompanied with seizures. The manifestations (facial dysmorphism and malformations) progress with age. Some patients with a low level mosaïcism are less severely affected.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


Tetrasomy 18p is a very rare structural chromosomal anomaly affecting multiple body systems and characterized clinically by craniofacial abnormalities, delayed development, cognitive impairment, changes in muscle tone, distinctive facial features, and rarely renal malformations.


Tetrasomy 21 is an extremely rare autosomal anomaly resulting from the presence of 4 copies of chromosome 21, characterized by features of trisomy 21 including developmental delay/intellectual disability, muscular hypotonia, short neck with redundant skin, brachycephaly, microcephaly, flat face, epicanthus, upslanted palpebral fissures, small ears, protruding tongue, single transverse palmar crease, brachydactyly, hypoplastic iliac wings, together with additional features such as prematurity, intrauterine growth retardation, high and broad forehead, hypertelorism. Haematological malignancies are also associated and may occur earlier than in trisomy 21.


Tetrasomy 5p is a rare chromosomal anomaly syndrome with variable phenotype principally characterized by developmental delay, growth retardation/short stature, hypotonia, seizures, ventriculomegaly, hand and foot anomalies (e.g. clinodactyly, overlapping toes) and mosaic pigmentary skin changes. Patients may also present minor dysmorphic craniofacial features (incl. macrocephaly, upslanting palpebral fissures, hypertelorism, abnormal auricles, anteverted nasal tip, midface hypoplasia).


Tetrasomy 9p is a rare autosomal anomaly characterized by pre- and postnatal growth retardation, psychomotor delay, mild to moderate intellectual disability, hypotonia, microcephaly, dysmorphic features (ocular hypertelorism, low-set, malformed ears, bulbous/beaked nose, microretrognathia, enophthalmos/micropthalmia, epicanthus, strabismus), cleft lip/palate, skeletal abnormalities (hypoplastic nails/distal phalanges, short stature, short neck, contractures), congenital heart defects, renal and urogenital malformations (renal hypoplasia, genital hypoplasia, cryptorchidism).


Tetrasomy X is a sex chromosome anomaly caused by the presence of two extra X chromosomes in females (48,XXXX instead of 46,XX).

Summary:
Epidemiology
Prevalence is unknown but only around 40 cases have been reported in the literature so far.
Clinical description
Tetrasomy X is associated with delayed speech, learning difficulties, developmental delay and facial dysmorphism. Although disease severity is variable, the learning difficulties and developmental delay are generally mild to moderate. Commonly associated facial features include hypertelorism, upslanting palpebral fissures, epicanthal folds and a flat nasal bridge. Other anomalies may include dental abnormalities, hypotonia and joint laxity, radioulnar synostosis, heart defects, hip dysplasia, and ovarian dysfunction. An increased susceptibility to infections during childhood has also been reported.
Etiology
Tetrasomy X is generally thought to arise as a result of successive maternal nondisjunction during meiosis.

                            Last update:
                            January 2010

                            - Expert reviewer(s):
                            Dr Natalie AYARI  - Dr A BERGE  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA


A form of rare hemochromatosis (HC) characterized by excessive tissue iron deposition of genetic origin and presenting with liver disease, hypogonadism, arthritis, diabetes and skin pigmentation.

Summary:
Epidemiology
Less than 50 cases have been reported in the literature. It is mainly found in Caucasian populations but has also been reported in Asia.
Clinical description
TFR2-related hemochromatosis concerns middle aged-adults but also adolescents and young adults (<30 years old). It resembles symptomatic HFE-related hemochromatosis and presents with liver disease, hypogonadism, arthritis, diabetes and skin pigmentation. Biochemical abnormalities include elevated serum iron, transferrin saturation and ferritin.
Etiology
It is due to mutations of the transferrin receptor 2 gene (TFR2) on chromosome 7. These mutations lead to hypohepcidinemia which in turn causes iron excess through increased intestinal iron absorption and iron release from spleen macrophages.
Diagnostic methods
Diagnosis is based on biochemical testing using serum transferrin saturation and serum ferritin, and on imaging testing for quantifying visceral iron overload (magnetic resonance imaging). Molecular genetic blood testing permits to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes: a) in younger patients: HJV or HAMP-related hemochromatosis and post-transfusional iron overload in the case of hematological diseases such as thalassemia major, sickle cell disease, and other rare iron-loading anemias b) in older patients: HFE-related hemochromatosis and other adult-onset rare forms of non-HFE-related hemochromatosis (SLC40A1-related HC, for example).
Genetic counseling
Genetic counseling should be offered to first-degree relatives of patients with genetically confirmed TFR2-related hemochromatosis. Particular focus should be given to siblings as they are at the highest risk (25%).
Management and treatment
Patients are treated by repeated phlebotomies that are performed weekly until the ferritin level reaches 50 µg/L, after which they are performed every 1-3 months.
Prognosis
Prognosis can be considered as good, provided that the patients are treated early, before the development of severe visceral complications (especially cirrhosis).

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Pr Graça PORTO | EuroBloodNet*

                                * European Reference Network


A rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (including long, downward slanting palpebral fissures, hypertelorism, posteriorly rotated ears, broad nasal bridge, short nose with a bulbous tip and anteverted nares, downturned corners of the mouth) as well as vertebral (occult spina bifida, hemivertebrae), brain (ventricular dilatation, agenesis of corpus callosum), cardiac (tetralogy of Fallot, ventricular septal defect) and gastrointestinal (short esophagus with intrathoracic stomach, small intestine, spleen and pancreas, anal atresia) malformations. There have been no further descriptions in the literature since 1991.


Thalidomide embryopathy is a group of anomalies presented in infants as a result of in utero exposure (between 20-36 days after fertilization) to thalidomide, a sedative used in treatment of a range of conditions, including morning sickness, leprosy and multiple myeloma (see these terms). Thalidomine embryopathy is characterized by phocomelia, amelia, forelimb and hand plate anomalies (absence of humerus and/or forearm, femur and/or lower leg, thumb anomalies). Other anomalies include facial hemangiomas, and damages to ears (anotia, microtia), eyes (microphthalmia, anophthalmos, coloboma, strabismus), internal organs (kidney, heart, and gastrointestinal tract), genitalia, and heart. Infant mortality associated with thalidomide embryopathy is estimated to be as high as 40%. Thalidomide is contraindicated in pregnancy and pregnancy prevention is recommended in women under treatment.


A form of thanatophoric dysplasia characterized by prenatal onset of growth deficiency of the limbs of less than 5%, bowed femurs (like a telephone receiver), shortened ribs, and platyspondyly. Fetal MRI can identify temporal lobe abnormalities and a narrow foramen magnum. Postnatally, distinctive facial features include macrocephaly, large anterior fontanel, frontal bossing, midface hypoplasia, proptosis, and low nasal bridge. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression.


A form of thanatophoric dysplasia characterized by prenatal onset of micromelia with straight femurs, platyspondyly, narrow thorax, and cloverleaf skull with increased risk of hydrocephalus and neurological complications. Fetal MRI can identify temporal lobe abnormalities and a narrow foramen magnum. Postnatally, distinctive facial features include macrocephaly, frontal bossing, midface hypoplasia, low nasal bridge, large anterior fontanel, and proptosis. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression.


A primary bone dysplasia with micromelia characterized by micromelia, macrocephaly, narrow thorax, and distinctive facial features. It includes TD, type 1 (TD1) and TD, type 2 (TD2), that can be differentiated from each other by femur and skull shape.

Summary:
Epidemiology
Thanatophoric dysplasia (TD) estimated incidence is about 1/20,000 to 1/50,000 births.
Clinical description
Characteristic morphological features are seen on prenatal ultrasounds. Late in the 1st trimester, shortening of the long bones is apparent on ultrasound along with increased nuchal translucency. In the 2nd trimester a marked growth deficiency (limb length below 5th percentile) is noted along with relative macrocephaly, a well mineralized skull, and narrow thorax with flattened vertebral bodies. Bowed ''telephone receiver'' femurs (in TD1), cloverleaf skull (in TD2 and a few cases of TD1) and polyhydramnios can also be seen. Neonates are macrocephalic with a large anterior fontanelle, frontal bossing, severe midface hypoplasia and proptosis. The thorax is narrow and bell-shaped. There is significant micromelia with redundant skin folds and brachydactyly with a trident hand configuration is common. Generalized hypotonia is present. CNS abnormalities can include temporal lobe dysplasia, hydrocephalus, and injury from critical foramen magnum stenosis. Rarely, cardiac and renal abnormalities have been reported as well as seizures.
Etiology
TD is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene (4p16.3) which cause overactivity of the FGFR3 protein, resulting in the disturbances in bone growth and other tissues that are characteristic of TD.
Diagnostic methods
Diagnosis is usually made in the 2nd to 3rd trimester but is possible earlier with short limbs identified during standard 1st trimester dimensional ultrasound. Molecular genetic testing can be used to screen for FGFR3 mutations and definitely diagnose TD.
Differential diagnosis
Differential diagnoses include homozygous achondroplasia, achondrogenesis (types 1A, 1B, and 2), SADDAN, short rib-polydactyly syndromes, osteogenesis imperfecta type 2, platyspondylic lethal skeletal dysplasias, dyssegmental dysplasia Silverman-Handmaker type, and campomelic dysplasia.
Antenatal diagnosis
Antenatal diagnosis is usually suspected by prenatal ultrasound and can be confirmed by molecular analysis of amniocytes, or by chorionic villus sampling (CVS), or recently by cell free fetal DNA.
Genetic counseling
TD is inherited autosomal dominantly but the majority of cases are due to a de novo mutation in the proband. Genetic counseling allows families who have already had one child with TD to know that recurrence rate is about 2%, so the likelihood of having a healthy child is high.
Management and treatment
Prenatally, treatment aims to avoid potential pregnancy and delivery complications. Postnatally, management should focus on the parents' wishes for provision of comfort-care for the newborn versus aggressive management. Respiratory support with a tracheostomy and ventilation is essential for survival in all infants. Hydrocephaly can be treated with the placement of a shunt. Suboccipital decompression can be done when needed to relieve craniocervical junction constriction. Antiepileptic drugs can be given to those with seizures. Hearing aids can be provided to those with hearing loss.
Prognosis
Prognosis is poor with death occurring in utero or shortly after birth in almost all cases. Death is likely due to respiratory insufficiency and/or spinal cord/brain stem compression. A few rare cases have been reported where patients survived into childhood with significant medical intervention.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Elaine PEREIRA


Theca steroid-producing cell malignant tumor of ovary, not further specified

A rare malignant sex cord stromal tumor of ovary of unknown histological lineage, occurring in adult women, characterized, in most cases, by manifestations of androgen excess (hirsutism, hair loss, amenorrhea, or oligomenorrhea) and, occasionally, Cushing syndrome.


Thiamine-responsive encephalopathy is a Wernicke-like encephalopathy (see this term) characterized by seizures responsive to high doses of thiamine.

Summary:
Epidemiology
Two cases have been described so far.
Clinical description
Clinical features include epilepsy, nystagmus, ophthalmoplegia and ataxia.
Etiology
The disease results from mutations in the SLC19A3 gene, encoding a thiamine transporter.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


Thiamine-responsive maple syrup urine disease (thiamine-responsive MSUD) is a less severe variant of MSUD (see this term) that manifests with a phenotype similar to intermediate MSUD (see this term) but that responds positively to treatment with thiamine.

Summary:
Epidemiology
MSUD has an estimated incidence of 1/150,000 live births. The thiamine-responsive type appears to be very rare.
Clinical description
Thiamine-responsive MSUD is poorly characterized. It appears to usually present after infancy with a phenotype very similar to that seen in intermediate MSUD (see this term). Manifestations include feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties. Like classic MSUD (see this term), physiological stress can result in acute decompensation with anorexia, nausea, vomiting (at all ages), ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute / focal dystonia and choreoathetosis (in adults) that can progress to stupor, coma and cerebral edema, if untreated. Thiamine (doses of 10-1000 mg per day) has improved the leucine tolerance in the few reported cases of this MSUD subtype, but some dietary branched-chain amino-acid (BCAA) restriction remains necessary.
Etiology
MSUD is due to mutations in the genes encoding 3 of the 4 subunits of branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a; BCKDHB (6q14.1), encoding E1b; and DBT (1p31), encoding E2 respectively. Mutations lead to an accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In thiamine-responsive MSUD, mutations in DBT predominate.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Bridget WILCKEN


Thiamine-responsive megaloblastic anemia syndrome

Thiamine-responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness.

Summary:
Epidemiology
TRMA syndrome has been reported in less than 80 cases worldwide. Its prevalence and incidence are unknown.
Clinical description
TRMA can present at any age between infancy and adolescence, although often not all key features are manifested at onset. TRMA is typically characterized by the triad of megaloblastic anemia responding to thiamine, sensorineural deafness, and non-type I diabetes mellitus. Clinical megaloblastic anemia manifestations may comprise hyporexia, lethargy, cephalalgia, pallor, diarrhea, and parasthesia in hands and feet. Other variable clinical signs include retinal dystrophy and optic nerve atrophy; short stature; cardiovascular abnormalities including congenital heart defects such as atrial and/or ventricular septal defect and arrhythmia/conduction anomalies; seizures and strokes. The variable phenotypic presentation of TRMA syndrome may cause a significant delay between the onset of symptoms and an accurate diagnosis.
Etiology
TRMA is an autosomal recessive disorder caused by heterogeneous mutations in the high-affinity transporter SLC19A2, located to chromosome 1q23.3. Nearly all patients identified are homozygous for the SLC19A2 mutations, but a small number of heterozygous mutations have been reported.
Diagnostic methods
Diagnosis of TRMA is based on clinical findings and can be confirmed by a bone marrow assessment showing megaloblastic anemia in association with erythroblasts with iron-filled mitochondria (ringed sideroblasts) and by molecular genetic analysis of the  SLC19A2 gene. Affected individuals have normal thiamine serum levels. Newborns should be screened by distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA).
Differential diagnosis
Differential diagnosis includes Wolfram syndrome, mitochondrial disorders such as Kearns-Sayre syndrome and Pearson syndrome (see these terms), as well as dietary vitamin B12 or folate deficiency.
Antenatal diagnosis
Prenatal diagnosis is possible by amniocentesis or chorionic villus sampling and specific gene analysis.
Genetic counseling
The SLC19A2 mutation is transmitted as an autosomal recessive trait. Genetic counseling should be offered to affected individuals and their families informing them of the possibilities of carrier testing for at-risk family members and the genetic risk for transmission to their children. Many patients are from consanguineous families, so it is difficult to ascertain whether all of the clinical features reported in some families are solely associated with the SLC19A2 mutation.
Management and treatment
Treatment is symptomatic and includes daily significant doses of thiamine (vitamin B1; 25-75 mg per day) to alleviate anemia and to possibly improve diabetes mellitus short-term and long-term outcome. Hearing loss appears irremediable and has a variable timeframe. There is still debate on whether prenatal and early thiamine treatment in affected individuals significantly delays the onset and reduces the hearing defect; several patients diagnosed at a young age have preserved hearing with thiamine treatment since a young age. Hearing aids and palliative care are recommended. Management includes regular hematological monitoring, glucose tolerance, urine, hearing, ophthalmologic and cardiac assessment.
Prognosis
Prognosis is variable. Once hearing is lost, it cannot be restored, whereas the anemia is generally reversible and the diabetes is often ameliorated for some time, and to some degree, with treatment. For patients with appropriate treatment and regular follow-up normal life expectancy should be achievable.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Ellis NEUFELD


Thickened earlobes-conductive deafness syndrome is characterized by microtia with thickened ear lobes, micrognathia and conductive hearing loss due to congenital ossicular anomalies. It has been described in two families. The mode of inheritance is autosomal dominant.


Thiel-Behnke corneal dystrophy (TBCD) is a rare form of superficial corneal dystrophy characterized by sub-epithelial honeycomb-shaped corneal opacities in the superficial cornea, and progressive visual impairment.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. Cases have been reported in Germany, the USA and in other countries.
Clinical description
Corneal erosions develop in the first and second decade of life and cause ocular discomfort and pain. The erosions recur and vision gradually becomes impaired.
Etiology
Thiel-Behnke corneal dystrophy appears to be caused by mutation in the TGFBI gene (5q31), like Reis-Bücklers corneal dystrophy. However, there appears to be genetic heterogeneity as another locus has also been identified on chromosome 10 (10q23-q24).
Diagnostic methods
Histological examinations reveal a variable thickness of the corneal epithelium. The epithelial basal lamina and Bowman layer display variable degenerative changes. Irregular subepithelial collagenous tissue is also found.
Differential diagnosis
TBCD is clinically similar to Reis-Bücklers corneal dystrophy (RBCD, see this term), but generally has a less severe course. Tissue examination or molecular genetic analysis can be used to differentiate TBCD and RBCD.
Genetic counseling
This entity has an autosomal dominant mode of inheritance.
Management and treatment
The pathologic corneal tissue can be excised surgically or with an eximer laser.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A very rare genetic necrotic bone disorder characterized clinically by painless swelling of the proximal interphalangeal joints associated with osteonecrosis of epiphyses followed by osteoarthritic changes, with onset before 25 years of age and often a benign course.


Thin ribs-tubular bones-dysmorphism syndrome

An extremely rare, lethal, primary bone dysplasia characterized by thin ribs, thin long bones, high-arched palate and facial features of frontal bossing and low-set, posteriorly rotated ears. Bilateral cryptorchidism may be also observed. There have been no further descriptions in the literature since 1990.


Thinking seizures is a rare neurologic disease characterized by seizures induced by specific cognitive tasks, such as calculation or solving arithmetic problems (e.g. Sudoku puzzle), playing thinking games (e.g. Rubik's cube, chess, cards), thinking, making decisions and abstract reasoning. Idiopathic generalized seizures are mainly involved, but partial epilepsies may, in rare cases, be observed.


A rare otorhinolaryngeal malformation characterized by a soft, fluctuant mass, abscess or draining tract along the anterior border of the lower half of sternocleidomastoid muscle, occasionally leading to development of retropharyngeal absces, acute suppurative thyroiditis, stridor, respiratory distress, odynophagia,and dysphagia. Anomaly occurs as a tract from the piriform sinus to the thyroid gland. A third branchial cleft fistula passes superficial to both the superior and recurrent laryngeal nerves, which is the main difference in comparison to the fourth branchial cleft fistula.


THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome

A rare, autosomal recessive, syndromic intellectual disability disorder characterized by global development delay, mild microcephaly, mild to severe intellectual disability and non-specific facial dysmorphism in association with variable multiple congenital anomalies including congenital heart defects, dental anomalies, cryptorchidism, renal and cerebral malformations. Short stature is frequent.

Summary:
Epidemiology
First described in two Hutterite families, there are now approximately 20 affected individuals reported worldwide.
Clinical description
Affected individuals have mild to severe intellectual disability and are non-verbal or have limited speech. The most relevant congenital anomalies include cardiac malformations (atrial and/or ventricular septal defects, patent ductus arteriosus), renal anomalies (unilateral agenesis or ectopic kidney), multiple teeth caries and/or malocclusion, cryptorchidism, anteriorly displaced anus, ventriculomegaly and corpus callosus dysgenesis. Short stature is reported in approximately half of individuals. Several recurrent craniofacial features have been described including mild microcephaly, tall forehead, high anterior hairline, short upslanting palpebral fissures, deep-set eyes, a long nose with low-hanging columella. The facial features are non-specific. More rarely, affected individuals could have hypergonadotropic hypogonadism (in females), seizures, low birth weight, feeding difficulties, hearing loss and/or eye abnormalities.
Etiology
The syndrome is caused by homozygous mutations in THOC6, encoding for a protein of the THO/TREX (transcription/export) complex, which is involved in the transcription of mRNA as well as the export of spliced mRNA from the nucleus; it is supposed to play a crucial role in both embryogenesis and human neurodevelopment.
Diagnostic methods
Diagnosis is based on molecular studies: for Hutterite communities, testing the specific c.136G>A variant can be considered; for non-Hutterite individuals, multigene panels for intellectual disability, chromosome microarray analysis, or exome array are indicated.
Differential diagnosis
Due to the non-specific characteristics of the syndrome, all disorders with intellectual disability and without other distinctive features should be investigated.
Antenatal diagnosis
Prenatal testing is possible when a pathogenic variant is already known in the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Carrier testing is possible where the pathogenic variant has been previously identified in a family member.
Management and treatment
Management requires a lifelong multidisciplinary approach, including a pediatrician, neurologist, otorhinolaryngologist (assessment for hearing loss), ophthalmologist, cardiologist, radiologist and gastroenterologist (to evaluate feeding problems and consider gastrostomy). Developmental assessments are needed to tailor medical services, develop an individualized education plan, and promote occupational therapy. Moreover, a behavioral assessment for signs of autism spectrum disorder is recommended. Annual evaluation of renal function should be considered in those with anomaly of kidney/urinary tract. Surgery is required in case of cryptorchidism while females older than 12 require an endocrine consultation. Need for family support (e.g. social work involvement, palliative care, home nursing) should be evaluated at each visit. No specific pharmacological therapy is available.
Prognosis
The course of the disease is non-progressive. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is possible. Need for life-long support from caregivers depends on the severity of intellectual disability.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Andrea ACCOGLI | ITHACA* - Dr Valeria CAPRA | ITHACA* - Dr Gianluca PICCOLO | ITHACA*

                                * European Reference Network


Thomas syndrome is characterised by renal anomalies, cardiac malformations and cleft lip or palate. It has been described in six patients. Transmission was suggested to be autosomal recessive.


A rare, genetic, skeletal muscle channelopathy characterized by slow muscle relaxation after contraction (myotonia).

Summary:
Epidemiology
Worldwide prevalence is estimated at 1/100,000.
Clinical description
Onset occurs early in life, usually in the first two decades, with myotonia potentially affecting every muscle after contraction, most frequently lower limb and hand muscles. Myotonia usually improves with exercise (e.g. after warm-up). Myotonia congenita may be inherited as an autosomal dominant (Thomsen disease) or recessive (Becker's disease) inheritance, with a more severe and earlier phenotype in recessively inherited disease.
Etiology
Disease is caused by loss of function mutations in the gene encoding the chloride channel, CLCN1 (7q34), that plays a role in muscle cell repolarization.
Diagnostic methods
The clinical diagnosis can easily be confirmed by electromyography (EMG), which reveals myotonic discharges in association with hyperexcitation of the muscle fiber membrane. EMG testing under exercise and cold stress allows detailed characterization of the myotonia and helps orientate the molecular diagnosis. Identification of mutations in the chloride channel gene can be considered as diagnostic.
Differential diagnosis
Steinert myotonic dystrophy, proximal myotonic myopathy and sodium channel channelopathies should be always considered in the differential diagnosis. Steinert myotonic dystrophy and proximal myotonic myopathy represent the most relevant differential diagnosis; these diseases present with fixed muscle weakness and wasting, and multisystem involvement, which are usually not associated to Thomsen and Becker disease, and occasionally may present with only myotonia. In addition, some degree of weakness may be observed in Thomsen and Becker disease, especially in later disease stages. Sodium muscle channelopathies may present with myotonia, which may be very similar to that reported in Thomsen and Becker disease or characterized by worsening with exercise, the so-called ''paradoxical myotonia'' (paramyotonia congenita).
Genetic counseling
The mode of transmission may be autosomal dominant (Thomsen myotonia) or autosomal recessive (Becker myotonia). Although some clinical and EMG clues may help distinguish Thomsen from Becker disease, genetic counselling should be proposed and the results of the molecular analysis should be interpreted with care as the same mutations have been associated with both dominant and recessive modes of transmission depending on the family studied.
Management and treatment
Treatment revolves around sodium channel blocking agents such as mexiletine hydrochloride (indication approved in Europe), carbamazepine, phenytoin, ranolazine or lamotrigine.
Prognosis
Myotonia congenital prognosis is relatively good, with normal life expectancy. Becker disease is considered more severe than Thomsen disease.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Lorenzo MAGGI  - Dr Renato MANTEGAZZA


A rare syndromic primary bone dysplasia characterized by short ribs with a narrow chest and thoracic dysplasia, mild rhizomelic shortening of the limbs, communicating hydrocephalus, and developmental delay. There have been no further descriptions in the literature since 1987.


Thoracic outlet syndrome (TOS) is a group of disorders characterized by paresthesias, pain and weakness of the upper extremities due to compression, tension or inflammation of the neurovascular bundle as it passes through the thoracic outlet. There are 3 forms of TOS with different clinical pictures and etiologies: neurogenic TOS (NTOS) that can be divided into true or disputed forms, arterial TOS (ATOS) and venous TOS (VTOS) (see these terms).

Summary:
Epidemiology
The diagnosis of TOS remains controversial so the true incidence is unknown. Neurogenic TOS is the most frequently observed form accounting for 95% of all cases with 99% of these being disputed NTOS.
Clinical description
Compression typically occurs at the interscalene triangle, the costoclavicular space between the first thoracic rib and clavicle, or the subcoracoid space beneath the pectoralis minor tendon causing pain, paresthesias and weakness in the upper extremities. Patients are unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes (the Roos test).
Etiology
Depending on the subtype, TOS is due to subclavian vein obstruction (in VTOS), subclavian artery compression (in ATOS) or lower trunk brachial plexus compression, scarring of scalene muscles, poor posture or a congenital anomaly (in NTOS).

                            Last update:
                            May 2013

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


Thoraco-abdominal enteric duplication is a rare, syndromic intestinal malformation characterized by single or multiple smooth-walled, often tubular, cystic lesions, which on occasion contain ectopic gastric mucosa, located in the thorax (usually in the posterior mediastinum and to the right of the midline) and in the abdomen. Infants usually present with respiratory distress and older patients with heartburn, abdominal pain, vomiting and/or melena. Vertebral anomalies in the lower cervical spine, with CNS involvement, are frequently present and complications, such as bowel obstruction, perforation and intussusception, have also been reported.


Thoracolaryngopelvic dysplasia is a short-rib dysplasia characterized by thoracic dystrophy, laryngeal stenosis and a small pelvis.

Summary:
Epidemiology
Prevalence is unknown but less than 10 cases have been reported in the literature so far.
Clinical description
Patients present with severe respiratory distress (requiring intubation) during the neonatal period. The rib shortening is less severe than in Jeune syndrome (see this term) and the thorax is characteristically small, narrow and bell-shaped. The pelvis is reduced in all dimensions and the combination of the thorax anomalies and the small pelvis give the appearance of a protruding abdomen. Subglottic stenosis has also been described but it remains unclear whether this is a congenital anomaly or is secondary to long-term intubation. In addition, several cases of thoracopelvic dysostosis (without laryngeal involvement) have been described, which could represent heterogeneous expression of the same syndrome or a distinct entity.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            November 2008


A rare primary bone dysplasia disorder characterized by a bell-shaped thorax, disproportionate short stature, pelvic hypoplasia, dislocatable radial heads and elongated distal fibulae. No acetabular spurs nor phalangeal cone-shaped epiphyses are present and osseous manifestations tend to normalize with age. There have been no further descriptions in the literature since 1988.


Thrombocythemia with distal limb defects is a rare, genetic syndrome with limb reduction defects characterized by thrombocytosis, unilateral transverse limb defects (ranging from absence of phalanges to absence of hand or forearm) and splenomegaly.


Thrombocytopenia with congenital dyserythropoietic anemia (CDA; see this term) is a rare hematological disorder, seen almost exclusively in males, characterized by moderate to severe thrombocytopenia with hemorrhages with or without the presence of mild to severe anemia.

Summary:
Epidemiology
The prevalence is unknown. At least 3 families have been described with thrombocytopenia with CDA and GATA1 mutations in the literature.
Clinical description
The disease affects mainly males as females are usually asymptomatic or have only mild symptoms. It presents in infancy or in neonates (in severe cases) with patients bruising easily along with further manifestations of thrombocytopenia including epistaxis, petechiae, ecchymoses, or splenomegaly. Anemia is often present but can range from mild to severe. Excessive hemorrhage and/or bruising can occur in some patients after trauma or spontaneously in others. Cryptorchidism has also been reported in several cases.
Etiology
The disease is caused by mutations in the GATA1 (Xp11.23) gene encoding GATA1, a transcriptional regulator involved in erythropoiesis and megakaryocytopoiesis. Different mutations found in this gene account for a variable phenotypic spectrum of disorders.
Diagnostic methods
Diagnosis is based on family history of the disease and laboratory findings. Blood count reveals thrombocytopenia, in some cases anemia, and very rarely neutropenia. Platelets often have functional abnormalities, shown by a defect in the aggregation response to agonists. Peripheral blood smear shows abnormal erythrocyte size and shape as well as paucity of platelets. Bone marrow biopsy can reveal dyserythropoiesis, dysmorphic erythroblasts, and dysplastic platelets and megakaryocytes. Molecular genetic testing can identify GATA1 mutations.
Differential diagnosis
Differential diagnosis includes myelodysplastic syndromes, thalassemias, Gilbert syndrome, hereditary spherocytosis, acute erythroid leukemia (see these terms), folate, iron or vitamin B12 deficiencies as well as infections such as AIDS, malaria (see this term), kala-azar or other acquired or inherited thrombocytopenias. Wiskott-Aldrich Syndrome (see this term) should also be excluded.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known GATA1 mutation.
Genetic counseling
The disease is inherited in an X-linked manner and genetic counseling is possible. Most females are asymptomatic carriers.
Management and treatment
Those with very mild symptoms do not require treatment. Thrombocytopenia related manifestations can be treated with platelet transfusions. For short-term mild to moderate bleeding, desmopressin may also be beneficial. Those with severe hydrops fetalis (see this term) related anemia will need an in utero transfusion and transfusions can be required after birth for those with severe anemia. Blood iron levels should be closely monitored in those undergoing regular transfusions. Bone marrow transplantation (BMT) can be considered in those with life-threatening manifestations. Antiplatelet agents, nonsteroidal anti-inflammatory agents and activities with a high risk of trauma should be avoided.
Prognosis
Prognosis depends on the severity of the disease. Quality of life may be affected in those with a serious form of the disease, and iron overload due to repeated blood transfusions to treat anemia can be very damaging if left untreated.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ