A rare congenital malformation syndrome characterized by bilateral absence/hypoplasia of the radii with presence of both thumbs, and thrombocytopenia. Additional manifestations can include cow's milk allergy, anomalies of the lower limbs, heart and genitourinary system.

Summary:
Epidemiology
The prevalence of thrombocytopenia-absent radius (TAR) syndrome is estimated at around 1/100,000-200,000 people.
Clinical description
Individuals with TAR syndrome almost always have bilateral absence or hypoplasia of the radii. The thumbs are always present, which is highly specific for TAR syndrome. Upper limbs may be more severely affected (hypoplasia or absence of the ulnae and/or humeri, fingers syndactyly, fifth-finger clinodactyly). Lower limbs are affected in almost 50% of cases with variable severity (hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, absence of the patella). The most severe limb involvement is tetraphocomelia. Thrombocytopenia is congenital or develop within the first few weeks to months of life. Usually, platelet counts remain low during the first two years of life; then, they increase but do not normalize. Additional recurrent manifestations include: cardiac anomalies (atrial and/or ventricular septal defect, patent foramen ovale), gastro-intestinal involvement (cow's milk allergy, increased susceptibility to gastro-enteritis), genitourinary anomalies (kidney agenesis or malrotation, horseshoe kidney, hydronephrosis, pyelectasis). Other rare manifestations include Mayer-Rokitansky-Kuster-Hauser syndrome, rib and vertebral anomalies, Langerhans cell histiocytosis, transient leukemoid reaction, acute myeloid or lymphoblastic leukemia. Cognitive development is usually normal.
Etiology
TAR syndrome is caused by compound heterozygosity for a null (most often a 1q21.1 deletion including RBM8A) and a hypomorphic RBM8A allele.
Diagnostic methods
Diagnosis is made on the clinical signs and confirmed by molecular genetic testing.
Differential diagnosis
The main differential diagnoses are other disorders associated with radial aplasia, with a genetic etiology (Holt-Oram syndrome, ESCO2-spectrum disorder, Fanconi anemia, RAPADILINO syndrome, SALL4-related disorders), or not (VACTERL association, thalidomide embryopathy, fetal valproate spectrum disorder).
Antenatal diagnosis
Antenatal diagnosis may be suspected by fetal ultrasound examination identifying radial anomalies, and confirmed by molecular genetic testing.
Genetic counseling
TAR syndrome is inherited in an autosomal recessive manner. Penetrance is complete, with variable expressivity. Several characteristics are unusual in autosomal recessive disorders: null alleles are rare and can occur de novo in the proband, the percentage of affected sibs is consequently lower than expected; hypomorphic alleles are common, therefore an apparent parent-to-child transmission can be observed resulting in pseudo-dominant inheritance. Biallelic carriers of hypomorphic variants are asymptomatic.
Management and treatment
There is no curative treatment for TAR syndrome. Symptomatic treatment of manifestations and prevention of complications include: early detection of thrombocytopenia, prevention of bleeding and hemorrhage, platelet transfusions in case of severe thrombocytopenia, surgical interventions if required to manage cardiac, urinary or skeletal malformations, avoidance of cow's milk.
Prognosis
Prognosis is variable and mainly conditioned by the severity of thrombocytopenia and its complications (intracranial, digestive hemorrhage). Cardiac defects, renal malformations, acute complications of cow's milk intolerance, acute leukemia can also affect the prognosis.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Dr Simon BOUSSION | ITHACA* - Pr Florence PETIT | ITHACA*

                                * European Reference Network


A rare genetic coagulation disorder characterized by marked bleeding tendency and posttraumatic bleeding with easy bruising, soft tissue and muscle bleeding, hemarthroses, and menorrhagia due to an increase of soluble thrombomodulin in plasma with subsequent protein C activation and reduction of thrombin generation within a potential thrombus. Abnormal laboratory findings include markedly elevated plasma thrombomodulin, reduced prothrombin consumption, and decreased thrombin generation.


An aggressive and life-threatening form of thrombotic microangiopathy (TMA) characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and organ failure of variable severity and is comprised of a congenital (cTTP) and acquired, immune-mediated (iTTP) form.

Summary:
Epidemiology
The prevalence of thrombotic thrombocytopenic purpura (including both acquired and congenital forms) is difficult to determine. Worldwide, the incidence for iTTP ranges from 1/165,000-1,000,000 and, in France the prevalence is estimated at 1/77,000. The prevalence of cTTP ranges from 1/ 60,000-2,500,000.
Clinical description
iTTP generally occurs in adulthood, whereas cTTP usually in the neonatal period, during childhood or in the setting of pregnancy. Onset is usually acute but early symptoms may include fatigue, purpura or ecchymoses, abdominal pain, arthralgia and myalgia, resembling a flu-like episode. Disseminated microvascular thrombosis leads to consumptive peripheral thrombocytopenia, MAHA and widespread organ injury associated with cerebral (headache, confusion, altered consciousness, coma, seizures, hemiparesis and visual disturbances), cardiac (arrhythmia, infarction, congestive heart failure and cardiac arrest) and gastrointestinal (nausea, vomiting, abdominal pain and diarrhea) manifestations. Purpura and petechiae are the most common bleeding manifestations. Renal involvement is usually mild. Fever occurs in less than 50% of patients. Patients with iTTP may suffer from only one episode, but relapses can occur in 30 to 40% of cases in the absence of preemptive therapies. A chronic and frequently relapsing disease course is more typical in those with cTTP, without prophylactic treatment.
Etiology
TTP is caused by a severely decreased activity (< 10%) of ADAMTS13, a metalloprotease involved in the cleavage of ultra-large von Willebrand factor multimers. In cTTP, ADAMTS13 deficiency is caused by homozygous or compound heterozygous mutations ADAMTS13 (9q34), whereas it is associated with the presence of anti-ADAMTS13 immunoglobulin G (IgG) antibodies in iTTP.
Diagnostic methods
First, the diagnosis of TMA must be evoked in a patient with MAHA and a negative direct antiglobulin test, associated with a peripheral thrombocytopenia, especially if there is an associated organ failure (cerebral, renal or cardiac involvement, abdominal pain). Once the diagnosis of TMA is made, TTP must be recognized. The diagnosis can be strongly suspected in a patient with TMA when thrombocytopenia is profound (platelet count < 30 x109/L) and when renal involvement is only mild (serum creatinine level < 2.27 mg/dL). However, the diagnosis of TTP can only be ascertained by an undetectable ADAMTS13 activity (activity < 10%). cTTP is characterized by a persistently severe ADAMTS13 deficiency with no identifiable anti-ADAMTS13 antibodies. The sequencing of ADAMTS13 gene then identifies bi-allelic mutations. Acquired, iTTP is associated with anti-ADAMTS13 antibodies in serum. In 20% of cases, antibodies may not be detectable, but ADAMTS13 activity normalizes after the acute phase.
Differential diagnosis
Differential diagnosis includes other TMAs (hemolytic uremic syndrome, TMA secondary to transplantation, chemotherapy, drug, HIV/AIDS, as well as HELLP syndrome) and other diseases including catastrophic antiphospholipid syndrome, severe sepsis, vitamin B12 deficiency, malignant hypertension and severe disseminated intravascular coagulopathy.
Genetic counseling
cTTP is inherited autosomal recessively and genetic counseling is suggested. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
Given the severity of the disease and the risk of sudden organ failure, management in intensive care units until platelet count recovery is recommended. The current standard of care consists of plasma exchange replenishing active ADAMTS13 from donors' plasma (and to a lesser extend removing anti-ADAMTS13 antibodies and pro-aggregant substances), immunosuppressive therapies (e.g. glucocorticoids and rituximab) to prevent ADAMTS13 antibody production, and caplacizumab. Caplacizumab is a nanobody that targets von Willebrand factor (VWF) and accelerates platelet count recovery and prevents worse outcomes. After recovery, patients benefit from long-term follow-up with regular assessment of ADAMTS13 activity. Where decreased ADAMTS13 activity is observed, a preemptive infusion of rituximab should be proposed.
Prognosis
With a rapid diagnosis and the current standard of treatment, the prognosis of the disease is usually excellent with a complete recovery in more than 95% of cases. However, in a substantial number of cases patients suffer neurocognitive disorders including chronic fatigue, problems of memory and concentration, as well as depression. These troubles still have no clear explanation, and significantly impact quality of life.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Paul COPPO


Thumb deformity-alopecia-pigmentation anomaly syndrome is a rare, genetic, congenital limb malformation syndrome characterized by short stature, sparse scalp hair, hypoplastic, proximally-placed thumbs, and skin hyperpigmentation with areas of 'raindrop' depigmentation. Presence of a single, upper central incisor has also been reported. There have been no further descriptions in the literature since 1988.


Thumb stiffness-brachydactyly-intellectual disability syndrome

A rare, genetic, congenital limb malformation syndrome characterized by bilateral thumb ankylosis, type A brachydactyly and mild to moderate intellectual disability. Patients present thumb stiffness and abnormalities of the metacarpal bones, frequently associated with mild facial dysmorphism and signs of obesity. There have been no further descriptions in the literature since 1990.


A rare disorder of the anterior segment of the eye characterized by chronic recurrent epithelial keratitis manifesting with groupings of small, slightly elevated, ovoid, grayish-white intraepithelial opacities, usually located in the central cornea. Patients present with photophobia, tearing, foreign body sensation, and blurred vision. The condition is typically bilateral, takes a relapsing-remitting course, and is mostly self-limiting after a few years.


Thymic carcinoma (TC) is a type of thymic epithelial neoplasm (see this term) characterized by a high malignant potential.

Summary:
Epidemiology
The exact prevalence or incidence is unknown. It represents 1% of the anterior mediastinal tumors and occurs in all ages but more frequently between the ages of 30 and 60 years. The male to female ratio is 1.5:1.
Clinical description
Patients can be asymptomatic but more often present with chest-related symptoms (cough, chest pain), phrenic nerve palsy, or superior vena cava syndrome. Contrary to patients with thymoma (see this term), myasthenia gravis or paraneoplastic syndromes are rarely observed.
Etiology
Etiology is unknown.
Diagnostic methods
Diagnosis is based on clinical findings and on radiological studies. Chest X-rays reveals a mediastinal mass. Computed tomography, magnetic resonance imaging (MRI), magnetic resonance angiography (angio-MRI) and/or positron emission tomography (PET) further evaluate the lesion. Tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy, is used to confirm a diagnosis of malignancy. Complete excision is required for definitive histologic typing. TC is composed of atypical cells of an invasive nature and lacks immature (or cortical) T cells. Several histologic subtypes are observed: the most common are squamous cell carcinoma, mucoepidermoid carcinoma and lymphoepithelioma-like carcinoma while rarer variants include clear cell carcinoma, basaloid carcinoma, spindle cell carcinoma, and anaplastic carcinoma. Extremely rare variants include papillary carcinoma, adenocarcinoma, and rhabdoid carcinoma. The diagnosis of thymic carcinoma is one of exclusion, as there are no morphologic, immunohistochemical, ultrastructural or cytogenetic/molecular features that are pathognomonic for this tumor. Histologically, the tumors may resemble carcinomas commonly arising in other organs. For this reason, the diagnosis can only be established by exclusion through careful demonstration on clinical history, clinical examination, and radiographic and endoscopic examination of the absence of a primary tumor elsewhere.
Differential diagnosis
Differential diagnoses include lymphoma, germ-cell tumors (see these terms), and other primary thymic malignancies and metastatic cancers.
Management and treatment
Treatment consists in total thymectomy and complete tumor excision usually accompanied by neoadjuvant or adjuvant therapy consisting of radiotherapy, chemotherapy, or both. In case of metastatic TC, platinum-based chemotherapy is the first-line treatment.
Prognosis
Prognosis is poor due to the high frequency of recurrences and metastases in the pleura, lung, lymph nodes, bone, brain, and liver. The survival rate at 5 years is 35%.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Saul SUSTER


Thymic epithelial neoplasms (TEN) are rare malignancies arising from the epithelium of the thymic gland. They comprise three sub-types: thymoma, thymic carcinoma, and thymic neuroendocrine carcinoma (see these terms).

Summary:
Epidemiology
TENs have an annual incidence of approximately 1/588,000. Thymoma is the most frequent subtype, while thymic carcinoma and thymic neuroendocrine carcinoma represent 1% and 2-4% of the anterior mediastinal tumors, respectively. The two latter have a higher malignant potential than thymoma. TENs usually occur in adults from 30 to 80 years of age, with a median age of 60 years, but they can also occur during childhood.
Clinical description
Most adult patients are asymptomatic, while in children nearly two thirds present with symptoms that include cough, chest pain, weight loss, fatigue and dyspnea. Many autoimmune syndromes are associated with TENs. Myasthenia gravis (see this term) is observed in 30-50% of thymoma cases. Phrenic nerve palsy and superior vena cava syndrome are usually observed in cases of thymic carcinoma.
Etiology
Etiology is unknown.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Saul SUSTER


Thymic neuroendocrine carcinoma is a type of thymic epithelial neoplasm (see this term) displaying evidence of neuroendocrine differentiation.

Summary:
Epidemiology
The exact prevalence or incidence is unknown. Thymic neuroendocrine carcinomas represent 2-4% of the anterior mediastinal tumors. More than 300 cases have been reported to date. Men are predominantly affected.
Clinical description
Many of the patients are asymptomatic but some present with chest-related symptoms such as cough, chest pain, weight loss, fatigue and dyspnea. Cushing's syndrome, multiple endocrine neoplasia, and, rarely, carcinoid syndrome (see these terms) are associated with this type of tumor.
Etiology
Etiology is unknown.
Diagnostic methods
Diagnosis is based on clinical findings, radiological studies (chest X-rays, computed tomography, magnetic resonance imaging (MRI), angiography (angio-MRI) and/or positron emission tomography (PET)), and on tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy. Three histological subtypes are observed: well-differentiated neuroendocrine carcinoma (formerly known as ''thymic carcinoid''), moderately-differentiated neuroendocrine carcinoma (formerly known as ''atypical carcinoid''), and poorly-differentiated neuroendocrine carcinoma (also known as small cell carcinoma of the thymus).
Differential diagnosis
Differential diagnosis includes lymphoma, germ-cell tumors (see these terms), and other primary thymic malignancies and metastatic cancers.
Management and treatment
Treatment consists of total thymectomy and complete tumor excision usually accompanied by post-operative radiotherapy and chemotherapy.
Prognosis
Thymic neuroendocrine carcinomas are aggressive tumors with a poor prognosis. Prognosis is dependent on the histological subtype with well-differentiated neuroendocrine carcinoma being the least aggressive subtype and poorly-differentiated neuroendocrine carcinoma being the most aggressive subtype with a median survival of 18 months. Recurrences and metastases are frequently observed. The 10-year survival is between 10% and 28% and depends on the treatment.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Saul SUSTER


A rare, malignant, primary thymic neoplasm originating from neuroendocrine cells, presenting as a mass within the anterior mediastinum. Patients typically present with nonspecific symptoms, such as chest pain, cough, shortness of breath, or in some cases, superior vena cava syndrome, although patients could be asymptomatic during the early stages or present with multiple endocrine neoplasia type I. Ectopic production of ACTH and serotonin can lead to Cushing syndrome and carcinoid syndrome, respectively.


This syndrome is characterised by intrauterine growth retardation, renal dysgenesis and a unilobed or absent thymus.

Summary:
Epidemiology
It has been described in three girls born to a nonconsanguineous couple.
Genetic counseling
The mode of transmission is unknown but autosomal recessive inheritance was suggested.

                            Last update:
                            September 2007


Thymoma is a thymic epithelial neoplasm (TEN; see this term), a rare malignancy that arises from the epithelium of the thymic gland.

Summary:
Epidemiology
It is the most common form of TEN and has an annual incidence of approximately 1/769,000. The male to female ratio is 1:1.4. Thymomas usually occur between the age of 30 and 70 years (with a median age of 50 years) but in some rare cases they can also occur during childhood.
Clinical description
While half of the patients are asymptomatic, the other half present with chest related symptoms such as dyspnea, chest pain, upper respiratory infection, fatigue, weight loss, and cough or pneumonia. Thymomas are often associated with myasthenia gravis (see this term), an autoimmune disorder that manifests with diplopia, ptosis, dysphagia, and weakness. Some patients may suffer from other autoimmune diseases such as systemic lupus erythematosus (SLE; see this term) and rheumatoid arthritis, hematologic syndromes such as red cell anaplasia and erythrocytosis, and other chronic diseases such as hypertension, diabetes mellitus, renal insufficiency and coronary artery disease. A history of second tumor may be present in some patients.
Etiology
Etiology is unknown.
Diagnostic methods
Diagnosis is based on clinical findings, radiological studies and pathologic examination of resected tissues. Chest X-rays may reveal a widened mediastinum or loss of the normal anterior clear space. Computed tomography, magnetic resonance imaging (MRI), magnetic resonance angiography (angio-MRI) and/or positron emission tomography (PET) can be indicated to further evaluate the lesion. Tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy, is necessary for diagnosis. Thymomas are currently divided according to the World Health Organization (WHO) into four histological subclasses: types A, B, AB, and C. Type A tumors are composed of spindle or oval epithelial cells. Type B tumors consist of round or polygonal epithelial cells and are divided into three subtypes (B1, B2, and B3) based on their various proportions of background lymphocytes and increase in cytologic atypia of the epithelial cells. Type AB tumors consist of type A thymoma features with a variably dense lymphocytic component. Type C tumors are characterized by cytologic atypia and loss of the organotypical characteristics of the thymus; the latter term is synonymous with thymic carcinoma (see this term). On cut section, the tumors are nodular and gray-white, can be multi-cystic and can contain calcifications or hemorrhage. Most of them are encapsulated and some may be invasive.
Differential diagnosis
Differential diagnoses include lymphoma, germ-cell tumors (see these terms), and metastatic cancers.
Management and treatment
In early stages, treatment consists of complete surgical excision (usually performed by median sternotomy). In advanced stages (stage II according to Masaoka staging system) and in high-risk histologic subtypes (B3), surgery is accompanied by additional adjuvant therapy (consisting of post-operative radiotherapy) or neoadjuvant therapy. Total thymectomy usually relieves myasthenia gravis symptoms.
Prognosis
In the majority of cases, thymomas have a favorable course and can be removed by complete surgical excision. However, relapses and / or pleural, peritoneal, pulmonary, bone, central nervous or hepatic metastases have often been observed, which highlights that thymomas are all potentially malignant neoplasms. The prognosis seems to depend on the type of treatment and the stage of the tumor at the time of diagnosis.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Saul SUSTER


A rare syndromic renal disorder characterized by renal, neurologic and thyroid disease, associated with thrombocytopenia. There have been no further descriptions in the literature since 1978.


Thyroid ectopia is a form of thyroid dysgenesis (see this term) characterized by an ectopic location of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.

Summary:
Epidemiology
Prevalence is estimated at about 1/7,000. Thyroid ectopia causes around two-thirds of thyroid dysgenesis and is twice as common in females as in males.
Clinical description
Clinical manifestations of thyroid ectopia are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. Goiter is always absent. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.
Etiology
Thyroid ectopia refers to an ectopic location of the thyroid gland. This occurs when a thyroid remnant is found along the normal pathway of the thyroglossal duct, which is the path of the developing thyroid as it descends from the base of the tongue to its final location in the neck. Ectopic thyroid tissue has been found inferior and superior to the hyoid bone and above the thyroid cartilage. No specific mutations have been identified in humans, although mutations in FOXE1 (TTF-2; 9q22) are associated with ectopic thyroid glands in mice.
Diagnostic methods
Imaging studies are required to confirm the diagnosis of ectopia.
Genetic counseling
Thyroid ectopia is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component. Around 2% of cases have been shown to be familial.
Prognosis
Without treatment thyroid ectopia results in severe intellectual deficit and short stature.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Thyroid hemiagenesis is a form of thyroid dysgenesis (see this term) characterized by an absence of half of the thyroid gland that is usually asymptomatic but may result in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.

Summary:
Epidemiology
Thyroid hemiagenesis is estimated to occur in 1/500-1/2,000 individuals.
Clinical description
In symptomatic cases, clinical features and signs may include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay may also occur.
Etiology
Thyroid hemiagenesis has been reported in mice with compound heterozygous FOXE1/NKX2-1 and PAX8 gene (14q13 and 2q12-q14) mutations.
Genetic counseling
Some familial cases have been reported, suggesting genetic factors but to date none have been identified in humans.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Thyroid hypoplasia is a form of thyroid dysgenesis (see this term) characterized by incomplete development of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.

Summary:
Epidemiology
Prevalence is estimated at around 1/28,000. Thyroid hypoplasia and athyreosis (see this term) combined account for one-third of cases of thyroid dysgenesis.
Clinical description
Clinical manifestations of thyroid hypoplasia are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment thyroid hypoplasia results in severe intellectual deficit and short stature.
Etiology
Familial cases of thyroid hypoplasia are caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in partial inactivation of the TSHR gene (14q31) can present with thyroid hypoplasia.
Diagnostic methods
Imaging studies are required to confirm the diagnosis.
Genetic counseling
Thyroid hypoplasia is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component. Around 2% of cases have been shown to be familial.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


A rare primary organ-specific lymphoma characterized by primary origin in the thyroid gland, sometimes involving cervical lymph nodes, and infrequently more distant sites. Diffuse large B-cell lymphoma is most common, followed by MALT lymphoma, and follicular lymphoma. More rare types include T-cell lymphomas, Burkitt lymphoma, or classic Hodgkin lymphoma. The condition is usually associated with Hashimoto thyroiditis. Patients typically present with a mass in the thyroid, with or without cervical lymphadenopathy. Hoarseness and dyspnea may occur, while constitutional symptoms are rare. Prognosis is favorable for patients with localized tumors.


Thyrotoxic periodic paralysis (TPP) is a rare neurological disease characterized by recurrent episodes of paralysis and hypokalemia during a thyrotoxic state.

Summary:
Epidemiology
It is most common in Asian males (with male-to-female ratios ranging from 17:1 to 70:1) during the third decade of life: the annual incidence in Chinese and Japanese thyrotoxicosis patients is estimated at around 1/50, whereas it is estimated at 1-2/1,000 among non-Asian thyrotoxicosis patients.
Clinical description
TPP manifests as recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Recovery occurs within 2-72 hours. Attacks typically occur at night and may be preceded by muscle cramps, aches and stiffness. Ocular, bulbar and respiratory involvement has also been reported but is rare. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Episodes only occur when patients are thyrotoxic but symptoms and classical signs of hyperthyroidism are often absent at the time of the first attack. TPP can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves' disease.
Etiology
The pathogenesis remains unclear. Genetic predisposition is thought to play a role in the pathogenesis of TPP and single nucleotide polymorphisms (SNPs) of the CACNA1S (1q32) and GABRA3 (Xq28) genes have been associated with TPP susceptibility in some Asian populations. Hypokalemia is the consequence of an extra- to intracellular potassium shift due to an increase in Na/K-ATPase pump activity, either as a direct response to thyroid hormone or indirectly via adrenergic stimulation, insulin or exercise.
Diagnostic methods
Biochemical studies are essential for diagnosis, with mild-to-severe thyrotoxicosis and hypokalemia during attacks being the major findings. Other anomalies may include hypophosphatemia and hypomagnesemia, without changes in acid-base balance. EMG reveals myopathic changes during attacks and muscle excitability anomalies after a prolonged exercise test. ECG anomalies are also noted. Thyrotoxicosis is the key finding for distinguishing TPP from other causes of hypokalemic periodic paralysis (HOP), such as familial HOP (FHOP; see this term), and from other hypokalemic disorders with a transcellular potassium shift, and excessive renal potassium wasting or gastrointestinal losses.
Differential diagnosis
The differential diagnosis may also include Guillain-Barré syndrome, transverse myelitis (see these terms), spinal cord compression and hysteria, as well as muscle weakness and fatigue associated with hyperthyroidism in patients with thyrotoxic myopathy or myasthenia gravis (see this term).
Genetic counseling
TPP usually occurs sporadically
Management and treatment
Management of TPP includes definitive control of hyperthyroidism, prevention of attacks with propranolol and avoidance of precipitating factors. Potassium administration during attacks may prevent cardiac arrhythmias and hasten the recovery from paralysis.
Prognosis
The prognosis for patients is good and TPP resolves when euthyroid status is achieved.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Savine VICART


Tibial aplasia-ectrodactyly syndrome is a rare condition characterized by congenital ectrodactylous limb malformations associated with tibial aplasia or hypoplasia.

Summary:
Epidemiology
The incidence is estimated to be approximately 1 in 1,000,000 live births.
Clinical description
The expression of the phenotype is highly variable and ranges from bilateral aplasia of tibiae and split-hand/split-foot deformity (tetramonodactyly or transverse hemimelia) to the mildest visible manifestation, hypoplastic big toes. Additional malformations may include distal hypoplasia or bifurcation of femora, hypo- or aplasia of ulnae, and minor anomalies such as aplasia of patellae, postaxial and intermediate polydactyly in association with split-hand deformity, and cup-shaped ears.
Etiology
Two susceptibility loci at 1q42.2-q43 and 6q14.1 have been identified, leading to the hypothesis that this syndrome fits the model of digenic inheritance.
Differential diagnosis
Overlap with the Gollop-Wolfgang syndrome (see this term) has been described.
Genetic counseling
The syndrome is generally inherited in an autosomal dominant manner with reduced penetrance. Autosomal recessive inheritance has also been proposed in some families.

                            Last update:
                            May 2008


Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome is a rare, genetic dysostosis syndrome, with marked inter- and intra-familial variation, typically characterized by triphalangeal thumbs, hand and/or foot polysyndactyly and/or absent/hypoplastic tibiae (associated with duplication of fibulae in some cases), although isolated triphalangeal thumbs have also been reported. It is often accompanied with remarkable short stature and additional features may include radio-ulnar synostosis and hand oligodactyly, as well as abnormal carpal and metatarsal bones.


Tibial muscular dystrophy (TMD) is a distal myopathy characterized by weakness of the muscles of the anterior compartment of lower limbs, appearing in the fourth to seventh decade of life.

Summary:
Epidemiology
TMD is highly prevalent in Finland (1/5,000) due to a founder mutation, making it the most common muscle disease in Finland. The disease has also rarely been identified in families in several other European countries.
Clinical description
TMD manifests after the age of 35 to 40 (rarely after the age of 60) as slowly progressive weakness and atrophy of the anterior tibial muscles with decreased dorsiflexion. Muscle involvement may remain asymmetrical for many years. After about 10 to 20 years, long toe extensors become involved causing foot drop, tripping and clumsiness while walking. Proximal limb muscles, mainly hamstring muscles, may be involved after the age of 60 to 70 and may necessitate the use of a cane and reduced walking distances. Extensor digitorum brevis muscles are spared and involvement of upper limbs is very rare. Neither cardiomyopathy nor respiratory failure has been encountered. TMD may present in a mild form (may remain unnoticed even in elderly individuals) or as aberrant phenotypic forms in about 9% of cases (proximal leg or posterior lower leg muscle involvement even at onset).
Etiology
TMD is linked to mutations in the TTN gene (2q31) encoding the protein Titin. The Finnish founder mutation (FINmaj) is located in the last exon 363(Mex6). Atypical presentations in Finnish patients have recently been explained by modifying second mutations in TTN. Seven other mutations of the TTN gene causing TMD have been identified in non-Finnish populations of which some C-terminal titin mutations can be recessive, manifesting the disease in homozygosity or in compound heterozygosity (usually with recessive truncating titin mutations). FINmaj mutation in homozygosity or in combination with truncating recessive titin mutations causes early onset autosomal recessive limb girdle muscular dystrophy (LGMD2J, see this term).
Genetic counseling
Mode of inheritance of typical TMD is autosomal dominant, with a 50% risk of transmission to offspring, while some forms of TMD may be autosomal recessive.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


An infectious disease characterized by central nervous system (CNS) involvement caused by the TBE virus (TBEV) and transmitted to humans principally by the bite of ticks from the Ixodes genus. The symptomatology is often biphasic, with the initial phase being associated with a nonspecific febrile illness and the second phase with meningitis, meningoencephalitis or meningoencephalomyelitis.

Summary:
Epidemiology
TBE is the most important tick-borne viral disease in the Northern Hemisphere (Europe and Asia), is endemic in 27 European countries, and represents a considerable disease burden. It is predominantly transmitted to humans by the bite of the Ixodes ricinus and Ixodes persulcatus ticks, or in some cases, by alimentary infection through the milk of infected animals. TBEV is generally restricted to endemic areas where the virus circulates among ticks and reservoir hosts. Over the past two decades, the incidence of TBE has risen across Europe, including at higher altitudes, and in regions previously considered virus-free. The highest incidence rates are reported from the Baltic states and Central Europe (>10/100,000 inhabitants per year). There are wide fluctuations in registered annual cases. Infection rates are elevated in the 45-64 years age group, with a male preponderance.
Clinical description
Clinical presentation partly (but not solely) depends on the TBEV subtype. In the majority of patients infected with the European subtype of TBEV, CNS inflammation is preceded by a febrile illness, resulting in a biphasic course of the disease. The first phase (which corresponds to viremia) presents with fever, fatigue, malaise, headache, and muscle and joint pain which occur in the absence of CNS inflammation. It usually lasts <1 week and is followed by an asymptomatic period lasting several days. The hallmark of the second phase of TBE is CNS involvement. Meningitis is the predominant manifestation in children (70%), whereas approximately 50% of adult patients develop meningitis, 40% meningoencephalitis, and 5-10% meningoencephalomyelitis. The disease is on average milder in children than in adults and has the highest severity in the elderly. The fatality rate in patients infected with the European TBEV subtype is up to 1%. Moreover, 5% of patients have permanent paresis and >30% suffer from postencephalitic syndrome. The Siberian subtype is associated with similar TBE course, but may persist as chronic viral infection. The Far Eastern subtype is associated with a usually more severe disease with monophasic course and higher fatality and neurological sequelae rates.
Etiology
TBE is caused by three main subtypes of TBEV (a member of the genus Flavivirus in the family Flaviviridae): European, Siberian and Far Eastern; recently, Baikal and Himalayan TBEV subtypes have also been reported.
Diagnostic methods
TBE is suspected on clinical signs and symptoms associated with a living or travel history of the patient in endemic zones. Diagnosis is confirmed by: i) clinical presentation of meningitis or meningoencephalitis; ii) elevated cerebrospinal fluid leukocyte counts (>5×106 cells/L); iii) demonstration of a recent infection with TBEV indicated by the presence of specific serum IgM and IgG antibodies or IgG seroconversion in paired serum samples.
Differential diagnosis
Differential diagnosis depends on the travel history of the patient and includes other arboviral and tick-borne diseases, as well as meningitis, meningoencephalitis or meningoencephalomyelitis of other etiology.
Management and treatment
Treatment is symptomatic. Vaccination of individuals living in or visiting to TBE endemic regions is recommended.
Prognosis
The fatality rate is up to 1% for the European subtype; 5% of patients have permanent paresis and >30% suffer from postencephalitic syndrome. Various nonspecific symptoms and cognitive and neuropsychiatric sequelae (i.e. apathy, irritability, memory and concentration disorders, altered sleep pattern, headache, hearing defects, visual disturbances, ataxia, and flaccid paresis or paralysis) may affect the patient's quality of life, and sometime require lifestyle changes.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Petra BOGOVIC  - Pr Franc STRLE


Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair.

Summary:
Epidemiology
Tietz syndrome has been reported in 7 families to date.
Clinical description
Affected cases have a pale skin, blue eyes and light blond to white hair with white eyebrows and eyelashes. They gradually gain some pigmentation often as freckles on sun-exposed areas. Hearing loss is always bilateral, congenital, sensorineural and profound. Psychomotor development is normal.
Etiology
The syndrome is due to a missense mutation or in-frame deletion of one amino acid in the basic domain of the MITF (3p14-p13) gene, coding a basic helix-loop-helix (bHLH) leucine zipper transcription factor, regulating melanocyte development and the biosynthetic melanin pathway. However, these types of mutations give rise to variable phenotype, ranging from Tietz syndrome to Waardenburg syndrome type 2 (see this term), with possible interactions with modifier loci.
Genetic counseling
Tietz syndrome is an autosomal dominant syndrome. Genetic counseling is recommended.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


A rare, multiple congenital anomalies syndrome with cardiac involvement as a major feature characterized by QT prolongation, congenital heart defects, syndactyly, facial dysmorphism and neurodevelopmental features. There are three clinical phenotypes recognized, the classical types that present with a prolonged QT interval and either with (TS1) or without (TS2) cutaneous syndactyly of fingers and toes. The atypical form (ATS) causes multi-system health concerns but not necessarily with prolonged QT.

Summary:
Epidemiology
To date more than 60 cases have been reported worldwide.
Clinical description
Timothy syndrome (TS) often manifests during the neonatal period. However, in many cases it is diagnosed later, between the ages of 2-4 years old. In TS1, cardiac concerns may become apparent under anesthesia during finger separation surgery. Typical cardiac manifestations in all TS types include a rate corrected QT interval >480 ms, functional 2:1 atrio-ventricular (AV) block associated with bradycardia, tachyarrhythmias and congenital heart defects (patent ductus arteriosus, patent foramen ovale, atrial or ventricular septal defects, tetralogy of Fallot, hypertrophic cardiomyopathy). Facial dysmorphia often includes round face, depressed nasal bridge, low set ears, thin vermilion of the upper lip, and hypoplasic premaxillary. Widely placed teeth with poor enamel is common. Hair is generally sparse. Cutaneous syndactyly is typical of TS1, and often noted in ATS individuals. In TS2, congenital hip abnormalities and/or hypotonia are often noted. Pulmonary health concerns include frequent pneumonia. Gastro-intestinal issues include severe constipation, and in some ATS children, complications of chronic constipation may require surgical removal. Immunodeficiencies are common. Endocrinological concerns includes unusual fluctuations in blood sugar levels resulting in life threatening hypoglycemia, primarily associated with infections, and sleep issues; some children may require growth hormones. Neuronal-developmental concerns can be profound, autism or autistic spectrum disorders are noted, delayed speech and other physical, mental and social developmental milestones are generally delayed.
Etiology
TS is due to mutations in the CACNA1C gene (12p13.33). The clinical phenotypes correlate with genotype. TS1 is specifically due to a G406R (c.1216 G>A) change in exon 8A. TS2 has the exact same G406R (c. 1216 G>A) change but in the alternatively spliced exon 8. ATS can be recognized by any CACNA1C change (excluding the G406R change) that causes typical multi-system health concerns.
Diagnostic methods
TS diagnosis is based on observed clinical features and molecular genetic testing confirmation.
Differential diagnosis
Non-syndromic autosomal Long QT syndrome, Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, Acquired Long QT syndrome, syndactyly and heart-hand related syndromes, autism associated syndromes.
Antenatal diagnosis
Echocardiography can often identify fetal distress secondary to cardiac finding of 2:1 AV Block or bradycardia. When the pathogenic CACNA1C variant has been identified in a family member, prenatal genetic testing is possible for at risk pregnancies.
Genetic counseling
Most cases arise de novo; however, in some cases, TS has been identified as an inherited autosomal dominant trait resulting from parental germline mosaicism.
Management and treatment
The main objective is to prevent ventricular fibrillation (VF) and possible sudden death. Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmia drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias. Drugs that prolong QT interval should be avoided, and all medical procedures requiring anesthesia should be performed with caution. Additional congenital heart defects, respiratory infections, hypoglycemia, and skeletal/smooth muscle anomalies should be managed according to standard protocols. Drugs and dietary practices that could lead to hypoglycemia should be avoided for patients treated with beta-blockers.
Prognosis
Without prompt and appropriate treatment for cardiac concerns, the disease is usually fatal in infancy and early childhood due to arrhythmias precipitated by infections, severe illnesses, hypoglycemia or from complications associated with anesthesia.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Peter SCHWARTZ  - Dr Katherine TIMOTHY


Titin-related limb-girdle muscular dystrophy R10

A form of limb-girdle muscular dystrophy that usually has a childhood onset (but can range from the first to third decade of life) of severe progressive proximal weakness, eventually involving the distal muscles. Some patients may remain ambulatory but most are wheelchair dependant 20 years after onset.


TMEM165-CDG is a form of congenital disorders of N-linked glycosylation characterized by a psychomotor delay-dysmorphism (pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi syndrome) with postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Additional features include facial dysmorphism (midface hypoplasia, internal strabism of the right eye, low-set ears, moderately high arched palate, small teeth), nephrotic syndrome, cardiac defects, and feeding problems. The disease is caused by mutations in the gene TMEM165 (4q12).


A rare congenital disorder of glycosylation characterized by chronic, non-progressive liver disease, manifesting as mild steatosis with elevated serum transaminases and alkaline phosphatase, hypercholesterolemia, and decreased coagulation factors and ceruloplasmin. Transferrin glycosylation pattern is consistent with a type 2 congenital disorder of glycosylation. Liver biopsy may show mild non-progressive fibrosis. Patients usually remain asymptomatic, although delayed psychomotor development and hypotonia have been reported in single cases.


Mitochondrial encephalo-cardio-myopathy due to TMEM70 mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.

Summary:
Epidemiology
Prevalence is unknown. To date fewer than 100 cases have been reported in the literature.
Clinical description
Neonatal onset of the disease is frequent and clinical symptoms include low birth weight due to prematurity or intrauterine growth retardation, hypotonia, apneic spells, respiratory failure requiring ventilator support, and hypertrophic cardiomyopathy. Most patients who survive the neonatal period have mild cranio-facial dysmorphism with low set ears, prominent nasal bridge and retrognathia, persisting muscular hypotonia and moderate psychomotor developmental delay. Hypospadias and/or cryptorchidism are present in 50 % of boys. Hypertrophic cardiomyopathy is non-progressive and may even disappear.
Etiology
Mitochondrial encephalo-cardio-myopathy due to ATP synthase deficiency is a result of an isolated decrease in the tissue content and activity of mitochondrial FoF1 ATP synthase caused by depressed biosynthesis of the enzyme. This enzyme defect is present in all tissues and is due to autosomal recessive mutations in the TMEM70 gene (8q21.11), encoding ancillary factor of ATP synthase biogenesis. The mutation c.317-2A>G is prevalent, particularly in the Roma population.
Diagnostic methods
The most important diagnostic tool for this disease is molecular genetic analysis which confirms the presence of pathogenic mutations in the TMEM70 gene. Diagnosis of the enzyme defect is based on biochemical methods (Blue Native electrophoresis and Western blot analysis) confirming the decreased presence of ATP synthase and/or decreased activity of ATP synthase (both synthetic and hydrolytic activities are decreased) in tissue biopsy or cultivated fibroblasts.
Differential diagnosis
Differential diagnoses include ATP synthase deficiency due to ATPAF2 mutation and other ATP synthase disorders including NARP/MILS syndrome (see this term). Mitochondrial encephalo-cardio-myopathy due to isolated ATP synthase deficiency should be considered in critically ill neonates, especially in those with early onset of hypotonia and hypertrophic cardiomyopathy accompanied with lactic acidosis and/or hyperammonemia.
Antenatal diagnosis
Prenatal diagnosis in affected families is available using molecular genetic testing.
Management and treatment
Treatment is reliant on early diagnosis and includes appropriate intensive care during the neonatal period and optimizing nutrition to prevent catabolism in patients who survive this period.
Prognosis
Mortality is high, usually in the neonatal period or during early childhood. Most of the patients who survive the neonatal period have persisting muscular hypotonia and moderate intellectual deficit. Treatment may improve the life expectancy of affected patients.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Josef HOUSTEK  - Pr Stanislav KMOCH


TMEM94-associated congenital heart defect-facial dysmorphism-developmental delay syndrome

A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, congenital heart defects, generalized hypertrichosis and dysmorphic facial features, most commonly triangular face, thick arched eyebrows, widely spaced eyes, posteriorly rotated low set ears, depressed nasal bridge, broad nasal root and tip, and pointed chin.


TNP03-related limb-girdle muscular dystrophy D2

A rare subtype of autosomal dominant limb-girdle muscular dystrophy ,with a variable age of onset, characterized by progressive, proximal weakness and wasting of the shoulder and pelvic musculature (with the pelvic girdle, and especially the ileopsoas muscle, being more affected) and frequent association of calf hypertrophy, dysphagia, arachnodactyly with or without finger contractures and/or distal and axial muscle involvement. Additional features include an abnormal gait, exercise intolerance, myalgia, fatigue and respiratory insufficiency. Cardiac conduction defects are typically not observed.


Tolosa-Hunt syndrome is an ophthalmoplegic syndrome, affecting all age groups, characterized by acute attacks (lasting a few days to a few weeks) of periorbital pain, ipsilateral ocular motor nerve palsies, ptosis, disordered eye movements and blurred vision usually caused by a non-specific inflammatory process in the cavernous sinus and superior orbital fissure. It has an unpredicatable course with spontaneous remission occurring in some and recurrence of attacks in others.


A neurodevelopmental teratologic syndrome due to prenatal exposure to toluene. The disease is characterized by prematurity, low birth weight, dysmorphic features (short palpebral fissures, deep set eyes, low set ears, mid-facial hypoplasia, flat nasal bridge, thin upper lip, micrognathia, spatulate fingertips and small fingernails), central nervous system dysfunctions (intellectual disability, microcephaly, language impairment, hyperactivity, visual dysfunction) and postnatal growth delay. Prenatal exposure to toluene occurs as a result of incidental occupational exposure or solvent abuse during pregnancy. The features of toluene embryopathy often overlap with those seen in fetal alcohol syndrome.


TOR1AIP1-related limb-girdle muscular dystrophy

A form of limb-girdle muscular dystrophy, presenting in the first or second decades of life, characterized by slowly progressive proximal and distal muscle weakness and atrophy. Additional manifestations include contractures of the proximal and distal interphalangeal hand joints, rigid spine, restricted pulmonary function, and mild cardiomyopathy.


Toriello Carey syndrome is a multiple congenital anomaly syndrome characterized by craniofacial dysmorphic features, cerebral anomalies, swallowing difficulties, cardiac defects and hypotonia.

Summary:
Epidemiology
At least 50 cases have been reported since the first description in 1988.
Clinical description
Main clinical signs include telecanthus, short palpebral fissures, small nose with anteverted nares, Pierre Robin sequence (micrognathia, glossoptosis and cleft palate), abnormally shaped ears, redundant neck skin and features of midline structural abnormalities with agenesis of corpus callosum, laryngeal anomalies and congenital heart defects. Short hands and hypotonia may also be observed. Patients have a moderate to severe intellectual disability.
Etiology
The etiology of Toriello-Carey syndrome is not fully understood, but there is evidence that this is a heterogeneous condition, with chromosome anomalies identified in approximately 20%, and at least two candidate genes identified: MN1 (22q12.1) which has been reported in a microdeletion and SATB2 (2q33.1), interrupted by a de novo balanced translocation in another patient.
Diagnostic methods
Imaging studies of the brain to determine if the corpus callosum is abnormal and physical examination paying particular attention to ocular spacing and palatal structure. A chromosomal microarray is indicated in any child with a Toriello-Carey phenotype.
Differential diagnosis
There are few conditions which include the combination of abnormalities of the corpus callosum and Pierre-Robin sequence. Two such conditions are Aicardi syndrome (in which Robin anomaly is a rare occurrence) and TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) (see these terms).
Antenatal diagnosis
The combination of corpus callosum anomalies and micrognathia should suggest the diagnosis.
Genetic counseling
If a chromosomal microdeletion/duplication has been ruled out, inheritance is autosomal recessive and the recurrence risk is likely 25%.
Management and treatment
Management is supportive.
Prognosis
The syndrome is associated with decreased life span.

                            Last update:
                            August 2012

                            - Expert reviewer(s):
                            Dr Helga TORIELLO


Torsade-de-pointes syndrome with short coupling interval

A rare variant of Torsade de pointes, a polymorphic ventricular tachycardia, which is characterized by a short coupling interval of the first TdP beat on electrocardiogram in the absence of any structural heart disease. It manifests in early adulthood with syncope, often results in ventricular fibrillation and shows a high risk of sudden cardiac death.


Torticollis-keloids-cryptorchidism-renal dysplasia syndrome is an extremely rare developmental defect during embryogenesis malformation syndrome characterized by congenital muscular torticollis associated with skin anomalies (such as multiple keloids, pigmented nevi, epithelioma), urogenital malformations (including cryptorchidism and hypospadias) and renal dysplasia (e.g. chronic pyelonephritis, renal atrophy). Additional reported features include varicose veins, intellectual disability and musculoskeletal anomalies.


A rare genetic disorder characterized by the triad of imperforate anus, dysplastic ears often associated with sensorineural and/or conductive hearing impairment, and thumb malformations. These features are often associated with other signs mainly affecting the kidneys and heart.

Summary:
Epidemiology
The prevalence of TBS is unknown. An estimate of 1/250,000 has been reported. More than 100 cases have been reported to date. Exact prevalence is difficult to determine because of overlap with other similar syndromes.
Clinical description
The clinical presentation is variable, even within the same family. Most patients present with imperforate anus (82%), dysplastic ears manifesting as overfolded superior helices and preauricular tags with hearing impairment (65%), and thumb malformations (89%), including triphalangeal thumbs, preaxial polydactyly, and rarely hypoplasia. Other common associated manifestations are renal dysfunction (27%), including end-stage renal disease (ESRD) (42%), with or without structural abnormalities, congenital heart disease (25%), foot malformations (52%) involving flat feet or overlapping toes, and genitourinary malformations such as hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, and cryptorchidism (36%). Rare manifestations are ophthalmological (iris coloboma, microphthalmia, lamellar cataract, and chorioretinal coloboma with loss of vision), renal (kidney agenesis/hypoplasia, polycystic kidneys), and cardiac (atrial or ventricular septal defect, tetralogy of Fallot, lethal truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus). Additional rare features are gastrointestinal (anal stenosis, chronic constipation, gastroesophageal reflux) and CNS-related including Duane anomaly (see this term), Type I Arnold-Chiari malformation, intellectual deficit (10%), behavioral disorders, cranial nerve palsy, and hypoplasia of the dorsal part of corpus callosum. Rib and mild vertebral anomalies, growth retardation, and congenital hypothyroidism have been reported in rare cases.
Etiology
TBS is caused by mutations in the SALL1 gene (16q12.1). Over 70 nonsense, frameshift, and splice mutations have been identified. Large or full deletions have also been described. Some patients with clinical TBS carry a causative mutation in SALL4 rather than SALL1.
Diagnostic methods
The clinical diagnosis is based on the characteristic clinical findings. However, some patients carry SALL1 mutations but present only with a subset of these anomalies. Identification of a mutation confirms the clinical diagnosis. Corresponding sequencing and qRT-PCR/MLPA techniques are clinically available to detect gene mutations. Array CGH/SNP array is recommended to determine the extent and gene content of larger deletions.
Differential diagnosis
Differential diagnoses include VACTERL/VATER association, Okihiro syndrome, and Goldenhar syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is available and usually requires identification of the disease-causing mutation in the family. However, if typical malformations are seen on prenatal ultrasound, complete analysis of the SALL1 gene is also possible from prenatal samples.
Genetic counseling
TBS follows an autosomal dominant pattern of inheritance and about 50% of cases are de novo. Genetic counseling should be provided.
Management and treatment
Treatment involves immediate surgery to correct imperforate anus, with subsequent surgery for severe malformations of the hands and feet. Routine management of congenital heart defects is recommended. Hemodialysis and possible kidney transplantation may be required. Early treatment of hearing loss is essential.
Prognosis
The physical prognosis depends on the severity of the associated renal and cardiac signs. A prognosis with respect to intellectual development is not possible.

                            Last update:
                            October 2013

                            - Expert reviewer(s):
                            Pr Jürgen KOHLHASE


An extended form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving 30% or more of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.


Toxic maculopathy due to antimalarial drugs is a rare, acquired eye disease, due to long-term exposure to chloroquinine (CQ) or hydrochloroquinine (HCQ), characterized by a slowly progressive, usually non-reversible, development of bilateral atrophic bull's-eye maculopathy (progressive loss of central vision acuity, reduced color vision and central scotoma), which in severe cases can spread over the entire fundus, leading to widespread retinal atrophy and visual loss.


Toxic oil syndrome is a rare intoxication, due to consumption of a rapeseed oil denatured with aniline 2%, characterized by generalized vascular lesions affecting all organs and vessels (including veins and arteries) and presenting with severe incapacitating myalgias, marked peripheral eosinophilia and pulmonary infiltrates.

Summary:
Epidemiology
Spain is the only country to have reported cases of this disease in the spring of 1981 and patients resided in fourteen Central and North West provinces. Almost 20,000 people have been recorded, with women under the age of 40 years being more frequently and severely affected than men.
Clinical description
While TOS can affect all organs and vessels (such as the lungs, peripheral nerves, muscles, skin, digestive tract, liver and pancreas) the main outcome is fibrosis of the lumen of the vessels, skin, peripheral nerves and intestines. The disease course can be characterized by three clinical phases: i) the acute phase (lasting approximately 2 months) with a presentation of severe lung edema, eosinophilia, rash and myalgia, ii) the intermediate phase (2-3 months) with dysphagia, cramps, severe myalgia, skin edema, pulmonary hypertension, paresthesia, major vessel thromboembolism and severe weight loss, iii) the chronic phase, where the skin edema evolves to scleroderma, and the neuromuscular manifestations into paresis and paralysis due to polyneuropathy. Liver disease and fibrosis in major organs such as the pancreas and intestines are also present in patients with the poorest prognosis.
Etiology
The cause of TOS is the consumption of commercial rapeseed oil denatured with 2% of aniline. It was originally sold for industrial use and during the epidemic of 1981 was marketed fraudulently for human consumption. It still remains unclear whether fatty acid esters of 3-(N-phenylamino)-1, 2-propanediol (PAP) can induce TOS or if they are simply markers of oil toxicity.
Diagnostic methods
The diagnosis is based on clinical findings as there are no laboratory tests available.
Differential diagnosis
In the initial phase, several interstitial lung diseases should be excluded. Differential diagnoses for the chronic phase of TOS include several autoimmune rare diseases such as idiopathic pulmonary arterial hypertension, scleroderma (see these terms) and inflammatory polyneuropathy. Myalgia-eosinophilia syndrome associated with tryptophan (see this term) is another differential diagnosis that should be considered.
Management and treatment
No specific treatment is available. Major clinical features, such as lung edema at the earlier phase, can be treated with supportive measures at intensive care clinical units. Steroids are administered for some immunological manifestations, but they are not always effective. Certain major chronic features, such as pulmonary hypertension, are currently treated with modern vasodilators but many patients may require lung and cardiac transplantation. No effective treatments are available for scleroderma or neurological manifestations.
Prognosis
The prognosis is highly variable. Of the 20,000 people affected, more than 300 died during the first few years and around 30% of survivors developed a chronic condition. Other TOS survivors can show a variety of symptoms such as muscle pain, cramps and asthenia, as well as increased cardiovascular risks, while others have recovered with no further health problems.

                            Last update:
                            June 2016

                            - Expert reviewer(s):
                            Pr Manuel POSADA DE LA PAZ


Infectious botulism is a form of botulism (see this term), a rare acquired neuromuscular junction disease, characterized by descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), produced in vivo leading to toxin-mediated infection. Infectious botulism includes wound botulism and intestinal toxemia botulism (infant botulism and adult intestinal botulism; see these terms).

Summary:
Epidemiology
Prevalence is unknown. So far, about 4,000 cases have been reported worldwide, infant botulism being the most frequently reported form.
Clinical description
Clinical manifestations are similar to other forms of botulism, in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea and vomiting). Fever may be present in wound botulism.
Etiology
Infectious botulism is due to BoNTs produced in vivo after colonization by C. botulinum and, very rarely, by neurotoxigenic strains of C. baratii and C. butyricum. Intestinal botulism is due to intestinal colonization and wound botulism is due to the contamination of a wound, but nowadays affects mainly intravenous drug users (IDUs). After spore germination and toxinogenesis, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Michel POPOFF


A cosmopolitan zoonotic disease caused in humans by the accidental ingestion of eggs or larvae of the ascarids Toxocara canis or Toxocara cati, the common round worm of dogs and cats respectively. The infestation can be asymptomatic or can present as visceral larva migrans caused by larval migration through major organs such as liver, lungs or central nervous system (manifesting with fever, cough, hepatomegaly, pneumonia or rarely encephalitis), or as ocular larva migrans caused by larval migration to the eye (manifesting as ocular inflammation and retinal scaring).


A rare congenital malformation characterized by either completely absent (agenesis), or severely underdeveloped (atresia) trachea. In both cases, the tracheal lumen is absent for at least a portion of its length, with no proximal-distal communication between the larynx and lower airways. Functionally and in terms of management, tracheal agenesis and tracheal atresia are equivalent.

Summary:
Epidemiology
The prevalence at birth is less than 1 in 50 000. There is a male predominance (2:1 male-to-female ratio).
Clinical description
Associated congenital malformations are present in 90% of cases, most frequently affecting the cardiovascular or gastro-intestinal systems and the genito-urinary tract. Prenatal imaging may show signs of CHAOS (congenital high airway obstruction syndrome), including enlarged lungs, flattened or inverted diaphragm, fetal hydrops, and ascites. Polyhydramnios may be present. Tracheoesophageal fistula may also be present and cause decompression of the fetal lungs, which may obscure prenatal imaging signs of airway obstruction or CHAOS. Postnatal signs include aphonia, respiratory effort without air movement on auscultation, and inability to place an endotracheal tube. In patients with tracheoesophageal fistula, esophageal intubation may allow temporary oxygenation. Severity of agenesis may be described using the Floyd classification (type I: proximal tracheal agenesis with distal tracheoesophageal fistula; type II: absent trachea with carina arising from esophagus and leading to bronchi; type III: absent trachea and carina with bilateral mainstem bronchi arising directly from esophagus).
Etiology
No clear genetic cause or environmental contributors have been identified.
Diagnostic methods
Postnatally, the condition should be suspected in neonates presenting with polyhydramnios, respiratory distress, cyanosis and no audible cry, and in those in whom tracheal intubation proves impossible due to anatomic airway obstruction at or below the glottis. The diagnosis of TA is confirmed by direct laryngoscopy and a helical computerized tomography (CT) scan of the airway. A failure to perform esophageal intubation or an esophagoscopy may confirm presence of tracheoesophageal fistula; in some cases, a flexible bronchoscope may be passed via the esophagus and fistula into the lower airways.
Differential diagnosis
The differential diagnosis includes laryngeal atresia, severe glottic web (e.g with 22q11.2 microdeletion syndrome), congenital tracheal stenosis and VATER/VACTERL syndrome.
Antenatal diagnosis
Tracheal agenesis should be suspected in any fetus with prenatal imaging suggestive of CHAOS, particularly if the proximal airway fluid column on MRI extends into the larynx or proximal trachea. If tracheoesophageal fistula is present, there may be no clear signs of tracheal agenesis on prenatal imaging.
Management and treatment
If prenatal diagnosis is possible, careful counseling of the parents about the prognosis and typical clinical course is essential. Planned ex utero intrapartum treatment (EXIT) procedure may allow placement of a low or mediastinal tracheostomy if adequate distal trachea is present on prenatal imaging. If a concurrent tracheoesophageal fistula is present, oxygenation and ventilation may be achieved temporarily via esophageal intubation. Reconstruction may use the esophagus as a neotrachea, with or without external splinting or endoluminal stenting; subsequent alimentary tract reconstruction may use gastric pull-up or bowel interposition. Cadaveric tracheal allografts, 3D-printed grafts, and autologous free tissue reconstruction may provide other tracheal reconstructive options once the trachealized esophagus allows somatic growth.
Prognosis
This malformation is usually fatal in newborns; however, very rare cases of survival of several years have been reported with use of the esophagus in tracheal reconstruction.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Dr Karthik BALAKRISHNAN


A rare idiopathic, benign respiratory disease characterized by submucosal cartilaginous and/or bony nodules presenting in the trachea with or without the involvement of the major bronchi; involvement is potentially anywhere along the anterior and lateral walls of the tracheobronchial tree with sparing the posterior walls.


TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay or regression, variable congenital heart defects (such as patent ductus arteriosus, atrial or ventricular septal defects, and double outlet right ventricle, among others), and dysmorphic features (including ptosis, epicanthal folds, abnormally set/dysplastic ears, low hairline or excess nuchal skin, wide-spaced/inverted nipples, umbilical hernia or diastasis recti, and digital anomalies). Additional variable manifestations are hyper- or hypotonia, seizures, hearing loss, cortical blindness, and optic atrophy. Brain imaging may show cerebral and cerebellar atrophy and hydrocephalus.


Transaldolase deficiency is an inborn error of the pentose phosphate pathway that presents in the neonatal or antenatal period with hydrops fetalis, hepatosplenomegaly, hepatic dysfunction, thrombocytopenia, anemia, and renal and cardiac abnormalities.

Summary:
Epidemiology
Less than ten cases have been reported in the literature so far, all involving children born to consanguineous parents of Turkish and Arabic origin.
Clinical description
Dysmorphic features (downward-slanting palpebral fissures, low-set ears, and cutis laxa) have also been described. The severity of the symptoms and outcome vary widely.
Etiology
The disorder is caused by mutations in the transaldolase gene (TALDO1, 11p15.5-p15.4).

                            Last update:
                            March 2009


Transcobalamin deficiency (TC) is a disorder of cobalamin transport that usually presents during the first few months of life and is characterized by megaloblastic anemia, failure to thrive, vomiting, weakness and pancytopenia.

Summary:
Epidemiology
To date, more than 40 cases of TC have been described in the literature.
Clinical description
TC typically manifests in the first few months of life. Patients present with one or more of the following signs: weight loss, failure to thrive, diarrhea, vomiting, lethargy, irritability, pallor, ulcers of oral mucous membranes and impaired development. Myoclonus, decreased reflexes in the lower extremities and toe-walking may be observed. Severe infections (i.e. Pneumocystis carinii, pneumococcal meningitis, Escherichia coli, urinary tract infection, Salmonella sepsis, aseptic meningitis and gastro-enteritis) in the first year of life are also reported. In rare cases, the disease may be asymptomatic. Metabolic stroke and peripheral neuropathy have been observed in one case.
Etiology
TC is caused by mutations in the TCN2 gene (22q12.2) which encodes transcobalamin, a transporter of cobalamin (vitamin B12). Cobalamin has an important role in the metabolism of both homocysteine and methylmalonic acid as a cofactor for methionine synthase and methylmalonyl-CoA mutase, respectively. Methionine synthase helps to maintain levels of methionine and its derivative, S-adenosylmethionine, which is required for neurotransmitter synthesis and methylation of DNA, RNA, lipids and proteins. It also prevents accumulation of homocysteine.
Diagnostic methods
Diagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid.
Differential diagnosis
Differential diagnosis includes inherited disorders of intestinal cobalamin absorption (Gräsbeck-Imerslund disease and congenital intrinsic factor deficiency); inborn errors of cellular cobalamin metabolism, in particular the forms resulting in combined homocystinuria and methylmalonic aciduria (cblC, cblD, cblF, cblJ and cblX); and pernicious anemia (see these terms).
Antenatal diagnosis
Prenatal diagnosis is based on genetic screening of TCN2 or incubation of amniocytes in medium lacking any exogenous source of transcobalamin supplemented with radiolabeled cobalamin followed by measurement of transcobalamin-bound cobalamin.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended.
Prognosis
TC is a severe, life-threatening and rapidly progressing disease. Treatment, started early, is highly effective and reverses the clinical and hematological manifestations of the disease. If left untreated, immunologic deficiency (marked hypogammaglobulinemia with absence of specific antibody production after antigenic stimulation) and neurological problems (severe intellectual disabilities, ataxia, and pyramidal deficit) can develop.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


A rare, genetic, benign disorder of cobalamin transport, due to variable degrees of transcobalamin I deficiency, characterized by mildly low to almost undetectable plasma transcobalamin I levels and slighly low to absent serum cobalamin levels. Normal methylmalonic acid and homocysteine serum values and absence of megaloblastic anemia are reported. No specific clinical manifestations are associated and patients are typically asymptomatic.


Transgrediens et progrediens palmoplantar keratoderma

A rare, isolated, diffuse palmoplantar keratoderma disorder characterized by red-yellow, moderate to severe hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands, feet and/or wrists and involving the skin over the Achilles' tendon (transgrediens), gradually worsening with age (progrediens) to include patchy hyperkeratosis over the shins, knees, elbows and, sometimes, skin flexures. Hyperhidrosis is usually associated. Histologically, either epidermolytic or nonepidermolytic changes may be seen.


Transient erythroblastopenia of childhood

A rare, benign, red cell aplasia of young children or infants characterized by a normocytic normochromic anaemia with severe reticulocytopenia in otherwise normocellular bone marrow, and a complete spontaneous recovery within 1-2 months after diagnosis. Neutropenia and thrombocytosis may be associated findings at diagnosis, and a history of a preceding viral illness is frequent. No organomegaly is observed.


Transient familial neonatal hyperbilirubinemia

A rare genetic hepatic disease characterized by very high serum bilirubin levels in a newborn, clinically presenting as jaundice during the first few days of life. The condition is usually self-resolving, although in some cases it can lead to kernicterus with corresponding symptoms (including lethargy, high-pitched crying, hypotonia, missing reflexes, vomiting, or seizures, among others), which may result in chronic disability and even death.


Transient hypogammaglobulinemia of infancy

A rare primary immunodeficiency characterized by a delay in the maturation of immunoglobulin production, leading to prolongation of the physiologic hypogammaglobulinemia of the newborn period beyond six months of age. Patients present recurrent respiratory infections, otitis media, bronchitis, gastroenteritis, or allergic symptoms in the first two to four years of life, before the condition resolves spontaneously. Some children may remain asymptomatic, and severe or life-threatening infections are rare. The capacity to synthesize specific antibodies in response to vaccines is usually normal.


Transient infantile hypertriglyceridemia and hepatosteatosis is a rare, genetic, hepatic disease characterized by massive hepatomegaly, moderate to severe, transient hypertriglyceridemia and hepatic steatosis (followed by fibrosis), manifesting in infancy with failure to thrive, vomiting, an enlarged abdomen and a fatty liver. Reduction or normalization of triglyceride serum levels occurs with advancing age.


A rare hematologic disease characterized by clinical and morphological findings indistinguishable from those of acute myeloid leukemia, typically occurring in newborns with Down syndrome. Peripheral blood and bone marrow blasts display features suggestive of megakaryoblasts. In addition to trisomy 21, acquired GATA1 mutations are present in blast cells. Patients may be asymptomatic or present with thrombocytopenia, less commonly other cytopenias, leukocytosis, hepatosplenomegaly, jaundice, ascites, respiratory distress, bleeding, and pericardial or pleural effusions. Most patients undergo spontaneous remission within the first three months of life, although some may develop life-threatening hepatic, renal, or cardiac complications.


Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes (NDM, see this term) characterized by hyperglycemia presenting in the neonatal period that remits during infancy but recurs in later life in most patients.

Summary:
Epidemiology
The prevalence of neonatal diabetes is estimated to be between 1/95,000 to 1/400,000 live births. About 50% of NDM cases are transient (TNDM) and 50% permanent (PNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.
Clinical description
Cardinal clinical manifestations include severe intrauterine growth retardation, hyperglycemia (within the first week of life beginning in the neonatal period and resolving usually by 18 months of age), and dehydration. The most commonly reported congenital abnormalities are macroglossia and umbilical hernia. A wide range of different associated clinical signs including, facial dysmorphism, deafness and neurological (as a rule no epilepsy), cardiac, metabolic, kidney or urinary tract anomalies are reported. Affected infants usually require insulin initially, but the need for insulin gradually declines with time. Developmental delay and learning difficulties may also be observed. Women who have had TNDM as infants are at risk for relapse during pregnancy. Ketoacidosis is generally absent (except in patients with KCNJ11 and ABCC8 mutations).
Etiology
TNDM is caused by 6q24 alterations consisting of paternal uniparental disomy, partial duplication of paternal origin, or relaxation of maternal imprinting in 6q24. All these alterations induce overexpression of imprinted genes at the 6q24 locus, most likely PLAGL1 (6q24-q25) and HYMAI (6q24.2). Heterozygous mutations in the KCNJ11 (11p15.1) and ABCC8 (11p15.1) genes account for 26% of cases. Homozygous or compound heterozygous ZFP57 (6p22.1) mutations have also been reported to cause TNDM.
Diagnostic methods
Diagnosis is based on the clinical signs of TNDM and hyperglycemia and is confirmed by laboratory findings showing abnormal plasma insulin concentrations and by molecular genetic testing.
Differential diagnosis
Differential diagnoses include permanent NDM, DEND syndrome (epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus), intermediate DEND, and Wolcott-Rallison syndrome (see these terms) as well as all other syndromic forms of neonatal diabetes mellitus.
Antenatal diagnosis
Prenatal diagnosis requires identification of a specific genetic defect in the family and is available clinically on a limited basis.
Genetic counseling
The family tree may be indicative of an imprinting disorder. Sporadic cases with de novo mutations have been reported, as well as autosomal recessive and autosomal dominant patterns of inheritance, complicating genetic counseling. In the case of (partial) uniparental disomy, the recurrence risk is probably close to zero. In partial duplication, there is a risk of recurrence.
Management and treatment
Early diagnosis and appropriate treatment are crucial. Initial treatment mainly involves rehydration and intravenous insulin. Some infants however do not require insulin therapy. Insulin can rapidly be switched to the subcutaneous route or to continuous insulin pump therapy and discontinued once blood glucose levels have stabilized. During relapse of DM, which is poorly characterized, some patients can be treated with diet alone but others require oral sulfonylurea or insulin.
Prognosis
Rapid catch-up growth is normally achieved through insulin treatment and normal height and weight is often reached by two years of age. Diabetes may recur in childhood, during puberty, or later in adulthood in about 85% of patients. Prognosis is generally good but is dependent on timely rehydration and adequate control of potential complications.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr Michel POLAK


Transient neonatal multiple acyl-CoA dehydrogenase deficiency describes a very rare condition where a maternal riboflavin deficiency causes an infant to present with manifestations similar to those seen in multiple acyl-CoA dehydrogenase (MAD) deficiency (see this term) such as poor suck, metabolic acidosis and hypoglycemia, but that resolves completely with oral riboflavin. In the one patient described haploinsufficiency of the human riboflavin transporter (hRFT1) was described in the mother.


Transient neonatal myasthenia gravis (MG) is a rare form of MG (see this term) occurring in neonates born to mothers who have the disorder or specific circulating autoantibodies.

Summary:
Epidemiology
Exact incidence data are not available. The disorder occurs in 10% to 20% of children born to mothers with myasthenia gravis.
Clinical description
In some cases, the mother may be asymptomatic. Severity is generally not correlated with maternal disease but possibly with maternal antibody titers. Onset is usually within the first hours of life. Transient neonatal MG manifests as hypotonia, feeding difficulties, weak cry, facial diplegia and respiratory difficulties in affected neonates. With the gradual decrease in maternally-derived antibodies, the symptoms usually resolve. Subsequent births to the same mother are also at risk of this disorder. Risk factors for the condition are currently not clear. Rapid treatment usually enables resolution of the condition by 2 months of age.
Etiology
The disorder is related to passive transplacental transfer of maternal anti-acetylcholine receptorantibodies (anti-AChR) or anti-muscle-specific tyrosine kinase antibodies (anti-MuSK) to the neonate. Circulating autoimmune antibodies are thought to damage the post-synaptic neuromuscular junction. The fetal onset form is related to antibodies directed against fetal AChR.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD


A rare renal tubulopathy secondary to urinary tract infection (UTI) and/or urinary tract malformation (UTM) characterized by renal tubular resistance to aldosterone, characterized by hyponatremia, metabolic acidosis, hyperkalemia and inappropriately high serum aldosterone concentration and clinically manifesting as dehydration, vomiting, and poor oral intake.

Summary:
Epidemiology
So far, less than 100 cases have been reported worldwide. Because of its association with underlying UTMs, there is a strong male preponderance with more than 80% of affected infants being males. Due to the non-specific manifestations, the true prevalence of transient pseudohypoaldosteronism (TPHA1) is possibly underestimated.
Clinical description
TPHA1 occurs exclusively during the neonatal or early infantile period (90 % during the first six months of life). The clinical course is transient, typically resolving with treatment of the UTI, and may range from asymptomatic to life-threatening. The clinical features are non-specific and include nausea, vomiting, poor activity and low oral intake. As a consequence, life-threating salt loss, hyperkalemia and hemodynamic compromise may occur.
Etiology
Risk factors for TPHA1 in infants with UTI include male sex, young age and urinary tract malformation. Young age may contribute to the development of TPHA1 through low renal mineralocorticoid receptor expression and physiological partial aldosterone resistance. Urinary tract malformation has been found to be associated with decreased expression of mineralocorticoid receptor and increase in mineralocorticoid receptor resistance. In addition, bacterial factors including bacterial endotoxins and host factors such as TGF-beta, INF-alpha, IL-1 and -6 have also been speculated to involve the pathogenesis of TPHA1 in infants with UTI.
Diagnostic methods
The diagnosis can be confirmed by the findings of inappropriately elevated serum aldosterone in the setting of hyponatremia with renal sodium wasting, hyperkalemia with impaired renal potassium excretion, and non-anion gap metabolic acidosis. Infants should be screened for UTI and UTMs.
Differential diagnosis
The differential diagnoses include patients with impaired renal function (chronic kidney disease stage III to V), pre-existing electrolyte imbalance, medications (Na channel blockers, mineralocorticoid receptor blockers, calcineurin inhibitors, angiotensin converting enzyme inhibitors) which may cause pseudohypoaldosteronism. In cases of recurrent or persistent pseudohypoaldosteronism, the differential diagnosis should include pseudohypoaldosteronism type 1.
Genetic counseling
TPHA1 is not an inherited condition; however, in the cases of recurrent or persistent pseudohypoaldosteronism after treatment, the genetic analysis for the genes responsible for PHA1 may be considered.
Management and treatment
Early recognition and prompt treatment is crucial for affected infants with life-threatening hyperkalemia, salt wasting, and acidosis. The mainstays of treatment include antibiotics for UTI, volume repletion with salt supplementation for hyponatremia and in some cases bicarbonate for correction of metabolic acidosis. The need for additional therapeutic measures, such as loop diuretics, beta2 agonist, ion exchange resins, and calcium gluconate are determined by the severity of hyperkalemia.
Prognosis
The outcome is typically favorable as TPHA1 resolves with treatment of dehydration and urinary tract infection; however, the prognosis for affected infants with life-threatening hyperkalemia, salt wasting, and acidosis depends on early recognition and prompt treatment.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Martin KONRAD | ERKNet* - Dr MinHua TSENG

                                * European Reference Network


A rare disorder of tyrosine metabolism characterized by tyrosinemia, moderate hyperphenylalaninemia, and tyrosiluria that usually resolve after 2 months of age. It shows no clinical symptoms and is detected upon newborn screening. It is often observed in premature infants.


Transitional cell carcinoma of the corpus uteri

A rare uterine cancer characterized by a usually intracavitary, friable, relatively well-circumscribed tumor located in the corpus uteri, with possible infiltration of the myometrium, composed, microscopically, of cells resembling urothelial transition cells, with a papillary or polypoid growth pattern, typically admixed with another type of carcinoma (frequently endometrial adenocarcinoma), generally manifesting with postmenopausal vaginal bleeding.


A rare disorder of pentose phosphate metabolism characterized by developmental delay and intellectual disability, delayed or absent speech, short stature, and congenital heart defects (such as ventricular septal defect, atrial septal defect, and patent foramen ovale). Additional reported features include hypotonia, hyperactivity, stereotypic behavior, ophthalmologic abnormalities (bilateral cataract, uveitis, strabismus), hearing impairment, and variable facial dysmorphism, among others. Laboratory analysis shows elevated plasma and urinary polyols (erythritol, arabitol, and ribitol) and urinary sugar-phosphates (ribose-5-phosphate and xylulose/ribulose-5-phosphate).


A rare vaginal malformation characterized by the presence of a complete or incomplete transverse septum at any level of the vagina (most frequently the upper or middle third), resulting from incomplete fusion between the Müllerian duct component and the urogenital sinus component of the vagina during embryogenesis. The condition is only rarely diagnosed in neonates or infants, unless it causes significant hydromucocolpos. Complete septa present with primary amenorrhea, cyclic pelvic pain, dyspareunia, or a pelvic mass consisting of accumulated menstrual blood, while incomplete septa may lead to dyspareunia and dysmenorrhea.


TRAPPC11-related limb-girdle muscular dystrophy R18

A form of limb-girdle muscular dystrophy characterized by childhood-onset of progressive proximal muscle weakness (leading to reduced ambulation) with myalgia and fatigue, in addition to infantile hyperkinetic movements, truncal ataxia, and intellectual disability. Additional manifestations include scoliosis, hip dysplasia, and less commonly, ocular features (e.g. myopia, cataract) and seizures.


A rare genetic mandibulofacial dysostosis characterized by bilateral symmetrical oto-mandibular dysplasia including underdeveloped cheekbones (malar hypoplasia), a very small low jaw (micrognathia) and downward-slanting palpebral fissures, coloboma of the lower eyelids, microtia, hearing loss and without abnormalities of the extremities. Intelligence is normal.

Summary:
Clinical description
Children present with characteristic facial dysmorphism with bilateral and symmetrical hypoplasia of the malar bones and infra-orbital rim (more than 80% of cases) and of the mandible (78% to 97%) (retrognathia), which results in dental malocclusion, often characterized by a limitation of mouth opening of varying severity. Predominant hypoplasia of soft tissues is observed in the malar bone, inferior orbital rim and cheek. Eye manifestations include downward-slanting palpebral fissures (89%-100%), lower eyelid colobomas between the external and middle thirds (54% to 69%), with absence of eyelashes on the outer third of the lower eyelid. Bilateral conductive hearing loss is frequent (83% to 96%). External ear abnormalities, such as microtia or anotia (77%) are often associated with atresia of the external auditory canals and anomalies of the middle ear ossicles (60%). Breathing and nutrition difficulties may arise during the early years because of the narrowness of the upper respiratory tract and limited mouth opening. Occasionally, there is high palate, cleft palate with or without cleft lip (21% to 33%) and unilateral or bilateral choanal stenosis or atresia (13%-25%). Less common manifestations include salivary gland abnormalities with subsequent dry mucosa, enchondromas and/or pretragal fistulas, spinal and cardiac anomalies. Intellect is typically normal, and disability or delayed motor development has been rarely reported.
Etiology
The syndrome is caused by mutations in the TCOF1 gene (5q32) encoding the nucleolar phosphoprotein, treacle, or in the POLR1C (6p21.1), POLR1D (13q12.2), POLR1B (2q14.1) genes coding for RNA polymerase I and III subunits. Of note, a similar phenotype of acrofacial dystosis has been associated with POLR1A.
Diagnostic methods
Diagnosis is based on clinical findings and complementary examinations. Molecular tests confirm the diagnosis.
Differential diagnosis
Differential diagnoses include Nager syndrome (acrofacial dysostosis) distinguished by limb preaxial defects, Miller syndrome distinguished by limb postaxial defects, oculo-auriculo-vertebral spectrum in its bilateral and slightly asymmetrical form, and Burn-Mckeown syndrome.
Antenatal diagnosis
Once a pathogenic variant is identified in a family, antenatal molecular diagnosis is possible by molecular analysis of chorionic villus samples (CVS) and amniotic fluid. Preimplantation testing is also possible. Antenatal ultrasound may show typical facial dysmorphism and bilateral ear abnormalities.
Genetic counseling
Transmission is principally autosomal dominant with 90% penetrance and variable intra- and extra-familial expressivity. The mode of inheritance can be autosomal recessive in case of pathogenic variants in POLR1C and POLR1D genes. Genetic counseling is complicated by the variable expression of the disease and should be discussed with a multidisciplinary antenatal diagnosis team.
Management and treatment
Management is multidisciplinary. In cases with postnatal respiratory distress, tracheostomy, non-invasive ventilation (NIV) or mandibular distraction should be discussed. Maxillofacial and plastic surgery can correct the soft tissue hypoplasia (facial recontouring with lipostructure), bone hypoplasia (surgical bone distraction, bone grafts), eyelid coloboma and cleft palate (surgical repair). The treatment of the limited opening of the mouth is very difficult. Specialist otorhinolaryngology surgery is required for the abnormalities of the middle ear (functional surgery) and the external ear (reconstruction of the auricles). Management of hearing impairment should be early (hearing aids and functional surgery) to aid normal development.
Prognosis
The prognosis for milder forms of the disease is favorable with adequate treatment.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Corinne COLLET | ITHACA*

                                * European Reference Network