TAR syndrome

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The TAR syndrome (after English thrombocytopenia-absent radius syndrome ), also radius aplasia-thrombocytopenia syndrome or thrombocytopenia-radius aplasia syndrome, is a hereditary malformation syndrome with typically missing spokes ( radius ) on both sides ( radius aplasia ) with a deficiency of the thumb of blood platelets ( thrombocytopenia ).

A patient with TAR syndrome was first described in 1929 by the Americans HM Greenwald and J. Sherman. In 1969, Hall summarized a total of 40 cases under the name " Thrombocytopenia with absent Radius " and thereby coined the term TAR syndrome. In 1988 Hedberg published the largest collection to date with a total of 100 described patients affected by the TAR syndrome.

genetics

In 2007, a microdeletion on chromosome 1 gene locus q21.1 ( 1q21.1 deletion syndrome ) was described as a necessary, but not sufficient, genetic change. The microdeletion could be detected in the affected patients and in 75% of the cases also in one parent. In a quarter of the cases the microdeletion arose again, a so-called de novo inheritance. Five years later, the patient was on a cohort of 53 to show that the second necessary condition, a so-called single nucleotide polymorphism (engl. Single nucleotide polymorphism SNP, short) in the gene RBM8A is. In 41 patients this SNP is in the 5'UTR range , in the other 12 patients the SNP is in the first intron of the gene. How these genetic changes are related to the development of a TAR syndrome has not yet been clarified. In addition, three cases are described in the literature in which it was not possible to detect one of the two SNPs.

The RBM8A gene codes for the Y14 protein. This is part of the exon junction complex , which plays a role in splicing , more precisely in nonsense-mediated mRNA decay .

If the microdeletion can be detected in one parent and one of the two SNPs in the other, the probability that a common child is affected by the TAR syndrome is 25%, comparable to a recessive inheritance.

Epidemiology

In the literature there are numerous individual case descriptions and case collections with up to 100 patients (see above), so that over 300 cases should be described in the literature. It is estimated that there are around 0.5-1 TAR cases in 100,000 live births. Across all studies, it has always been shown that more women are affected by the TAR syndrome than men (for an overview of the gender ratio, see Table 2).

Symptoms

The following changes are always present:

  • Thrombocytopenia (lack of blood platelets ) and thus an increased tendency to bleed. Thrombocytopenia is particularly pronounced in the first few years of life. Patients who carry the SNP in the 5'UTR of the RBM8A gene are affected by more pronounced and protracted thrombopenias compared to patients with SNP in the first intron. In many cases, thrombopenia resolves into adulthood. The severity of the bleeding tendency varies. Life-threatening bleeding (e.g. intracranial bleeding) can occur.
  • Bilateral (bilateral) lack of the spoke ( radial aplasia ), while the thumb is always present and functions normally. Characterized deviation of the hand radially (thumb Windwärts) with clubhand -Fehlstellung. As a result, the ulna is always shortened and bent; it is also missing in about 20%. The upper arm bone (humerus) is usually shortened and dysplastic (malformed). Elbow, shoulder and wrist are restricted in movement.

Other changes are also common:

  • Leukemia-like changes, with massive increases in white blood cells ( leukocytes ). This occurs especially immediately after birth. However, there is no leukemia and no treatment is required. The number of leukocytes normalizes within the first few weeks of life.
  • Anemia . Comparable to thrombopenia, anemia is often more pronounced in patients with SNP in the 5'UTR. It is unclear here whether it is more a consequence of increased bleeding and thus a loss or whether it is caused by an educational disorder.
  • Frequently cow's milk allergy or intolerance, often caused by diarrhea and increased thrombocytopenia and leukocytosis, often with eosinophilia . The symptoms also improve in the course of development and hardly exist in adults.
  • In up to 50% of the cases accompanying dysplasias on the lower extremities, especially hip dysplasia , coxa valga , knee joint subluxation, patellar dysplasia with dislocation, knee stiffening and misalignments of the feet and toes.
  • Mostly short stature
  • Heart defects in about a third, especially Fallot tetralogy and atrial septal defect
  • Occasional ptosis of the eye . A glaucoma is described, but this may cause intraocular bleeding.

Differential diagnosis

Fanconi anemia must be distinguished, especially in the first months of life with a tendency to bleed and thrombocytopenia , otherwise there are similarities with Holt-Oram syndrome and Roberts syndrome . Tetra phocomelia- thrombocytopenia syndrome must be viewed as part of the TAR syndrome, not as a syndrome on its own.

In TAR syndrome, there is no motor development disorder or neurological impairment per se. The beginning of the run is usually restricted by the lack of support. Mental development is normal, retardation is probably always a result of intracranial bleeding in the first months of life.

therapy

Only symptomatic therapies are available for the treatment of TAR syndrome. Severe thrombopenias and anemia can be treated with blood transfusions . In particular, the transfusion of platelets is indicated in acute bleeding events.

Surgical treatment of the malformations, especially of the upper extremity, depends on the degree of the malformation.

literature

Individual evidence

  1. ^ HM Greenwald, J. Sherman: Congenital essential thrombocytopenia. In: Am J Dis Child. 38, 1928, p. 1245
  2. ^ JG Hall, J. Levin, JP Kuhn, EJ Ottenheimer, KA van Berkum: Thrombocytopenia with absent radius (TAR) . In: Medicine . tape 48 , no. 6 , November 1969, ISSN  0025-7974 , p. 411-439 , PMID 4951233 .
  3. ^ VA Hedberg, JM Lipton: Thrombocytopenia with absent radii. A review of 100 cases . In: The American Journal of Pediatric Hematology / Oncology . tape 10 , no. 1 , 1988, ISSN  0192-8562 , p. 51-64 , PMID 3056062 .
  4. ↑ E. Klopocki, H. Schulze u. a .: Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. In: American Journal of Human Genetics Volume 80, Number 2, February 2007, pp. 232-240, ISSN  0002-9297 . doi: 10.1086 / 510919 . PMID 17236129 . PMC 1785342 (free full text).
  5. ↑ a b Cornelis A. Albers, Dirk S. Paul, Harald Schulze, Kathleen Freson, Jonathan C. Stephens: Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome . In: Nature Genetics . tape 44 , no. 4 , February 26, 2012, ISSN  1546-1718 , p. 435-439, S1-2 , doi : 10.1038 / ng.1083 , PMID 22366785 , PMC 3428915 (free full text).
  6. ↑ Maximilian Jameson-Lee, Katherine Chen, Ellen Ritchie, Tsiporah Shore, Omar Al-Khattab: Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature . In: Hematology / Oncology and Stem Cell Therapy . doi : 10.1016 / j.hemonc.2017.02.001 ( elsevier.com [accessed July 12, 2017]).
  7. ↑ Ali Houeijeh, Joris Andrieux, Pascale Saugier-Veber, Albert David, Alice Goldenberg: Thrombocytopenia-absent radius (TAR) syndrome: a clinical genetic series of 14 further cases. impact of the associated 1q21.1 deletion on the genetic counseling . In: European Journal of Medical Genetics . tape 54 , no. 5 , September 2011, ISSN  1878-0849 , p. e471-477 , doi : 10.1016 / j.ejmg.2011.05.001 , PMID 21635976 .
  8. ↑ a b c d Georgi Manukjan, Hendrik Bösing, Markus Schmugge, Gabriele Strauss, Harald Schulze: Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome . In: British Journal of Hematology . August 31, 2017, ISSN  1365-2141 , doi : 10.1111 / bjh.14913 , PMID 28857120 .