Advertisement

Peer Reviewed

Photoclinic

Thrombocytopenia and Absent Radii Syndrome

Volume 60 - Issue 9 - September 2020

AUTHORS:
Krista Perez, BS • Shailendra Saxena, MD, PhD

AFFILIATIONS:
Creighton University School of Medicine, Omaha, Nebraska

CITATION:
Perez K, Saxena S. Thrombocytopenia and absent radii syndrome. Consultant. 2020;60(9):30-32. doi:10.25270/con.2020.05.00014
Received January 9, 2020. Accepted April 24, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.
CORRESPONDENCE:
Shailendra Saxena, MD, PhD, Department of Family Medicine, Creighton University School of Medicine, 7500 Mercy Rd, Omaha, NE 68124 (ssaxena820@gmail.com)

 

A 3-year-old boy presented for a well-child visit with a history of thrombocytopenia and absent radii (TAR) syndrome.

History. The patient had been born via cesarean delivery due to a prenatal diagnosis of TAR syndrome. At the time of birth, his platelet count was 22 × 103/µL, and he received a platelet transfusion. He had hyperbilirubinemia for which he had received phototherapy.

At the well-child visit, the mother has no health concerns about her son and states that he has been meeting all developmental milestones. She reported not having the child vaccinated, stating that the doctors at another hospital were unsure about how he would react to the vaccines. She noted that the patient recently had had his port removed, which had been used for platelet transfusions, since he is no longer considered to be at high risk for thrombocytopenia.

Physical examination. At presentation, the patient was active and alert, with normal neurologic development for age. His head was round and atraumatic, with a slightly prominent forehead; the rest of the ear, nose, and throat examination findings were unremarkable. The lungs were clear to auscultation bilaterally, and the heart was in regular rate and rhythm with no murmurs, rubs, or gallops.

Upper extremity examination revealed bilateral radial aplasia and ulnar aplasia with radial deviation (Figure 1). The thumbs were intact. The patient also had lower extremity deformities, with bilateral genu varum (Figure 2).

 

Figure 1
Figure 1. The patient presented with radial and ulnar aplasia.

Fig 2
Figure 2. The patient also presented with genu varum.

Discussion. TAR syndrome was first described in 1929 as a subset of Fanconi anemia and was determined to be its own syndrome in 1969.1 TAR syndrome is a condition that causes hypomegakaryocytic thrombocytopenia and aplasia of the radii. This thrombocytopenia typically resolves as patient enters early childhood.1

TAR syndrome is believed to be caused by an autosomal recessive mutation of the RNA binding motif protein 8A gene (RBM8A) on 1q21.1.2 This is thought to cause an exon-junction complex dysfunction and reduces RNA binding motif protein 8A, which affects the development of certain tissues.3,4 The inheritance of this mutation shows incomplete penetrance and variable expressivity.5 However, newer evidence suggests that this mutation is not enough to cause TAR syndrome, so it is thought that another uncharacterized mutation may be associated with the condition.6

Diagnosis. TAR syndrome is usually diagnosed prenatally via ultrasonography, which shows bilateral radial aplasia, club hands, and intact thumbs. After these findings are seen on ultrasonography, a cordocentesis is performed at 16 weeks in order to obtain a platelet count.7 Once diagnosed, pregnant women must be counseled on the importance of having a cesarean delivery to prevent intracranial hemorrhage as the baby goes through the birth canal.7

Presentation. TAR syndrome has a prevalence of 1 in 240,000 people and presents with varying severity of upper extremity deformities, from solely absent radii to complete phocomelia. The most common presentation of TAR syndrome is bilateral radial aplasia and thrombocytopenia of less than 50 × 103/µL at birth. Persons with TAR syndrome will have an intact thumb; this is an important distinction between TAR syndrome and Fanconi anemia.4 TAR syndrome is also commonly associated with other defects, including malformation of the ulnar bone or humerus. Some cases may present with abnormal knees, phocomelia of the lower extremities, dislocated hips, and cardiac defects such as tetralogy of Fallot, atrial septal defect, or ventricular septal defect.6-8 TAR syndrome can also include micrognathia, prominent forehead, and low-set ears.9 Associated intellectual disability is uncommon, but when it does occur it is usually a result of cerebral hemorrhage.

Thrombocytopenia is very severe within the first year of life, but over several years of life, the platelet count improves and eventually normalizes.6 The most common presentation of thrombocytopenia in TAR syndrome is intracerebral and gastrointestinal tract bleeding.1 The thrombocytopenia is a hypomegakaryocytic thrombocytopenia, with bone marrow samples showing normal cellularity with either absent or very few and immature megakaryocytes.2,6,10 It is believed that the bone marrow is not responsive to thrombopoietin, given that the thrombopoietin level is elevated in these patients.11

Differential diagnosis. The differential diagnosis of TAR syndrome includes Holt-Oram syndrome, Roberts syndrome, and Fanconi anemia. Holt-Oram syndrome and Roberts syndrome both present with hypoplastic radii, but they can easily be differentiated from TAR syndrome given that they both do not have hematologic manifestations and that they both do feature anomalies of the thumb, which are not seen in TAR syndrome. Roberts syndrome also is associated with other anomalies that are not commonly seen in TAR syndrome, such as cleft lip, fusion of the fingers, and an increase in lower limb deformities. Fanconi anemia differs from Holt-Oram syndrome and Roberts syndrome in that it does have hematologic manifestations, usually pancytopenia that develops in childhood rather than the thrombocytopenia present at birth in TAR syndrome.1

In cases of isolated amegakaryocytic thrombocytopenia, congenital amegakaryocytic thrombocytopenia (CAMT) must be considered among the diagnoses, but CAMT does not present with the radial dysplasia that is characteristic of TAR syndrome.12

Management. Patients with TAR syndrome are usually nonreactive to thrombopoietin, since thrombopoietin levels are usually elevated, and thus they must be treated with platelet infusions. One must also be concerned about alloimmunization and infection, so it is best to avoid platelet transfusions in individuals whose platelet counts exceed a threshold of 10/nL.5,10 This usually requires the insertion of a central venous port to avoid repeated venipuncture.10

Parents must be educated on the avoidance of cow’s milk, since up to 62% of persons with TAR syndrome have cow’s milk intolerance. This ranges from poor weight gain or vomiting to gastroenteritis resulting in exacerbations of thrombocytopenia and increasing the risk of gastrointestinal tract bleeding.6

Orthopedic management depends on the severity of the deformity and could include total knee arthroplasty and the use of adaptive devices. The authors of one small retrospective chart and radiograph review of 23 patients with TAR syndrome found that orthotics and prosthetics were generally rejected for the upper extremity deformities, since most patients had adapted and could perform tasks without prostheses, but devices to aid in buttoning, feeding, and toileting were well tolerated.13 Overall, surgical intervention was seen as less optimal in these patients than the use of an adaptive device.

Survivability of the disease often plateaus at the age of 5 years at 78%.8

Summary. TAR syndrome is a rare disorder that results in severe thrombocytopenia, as seen in the case of the patient described here with a platelet count of 22 × 103/µL at birth, as well as severe upper extremity deformities ranging in severity of solely radial aplasia to complete phocomelia. The diagnosis is usually made prenatally via ultrasonography showing the radial aplasia, and cesarean delivery is scheduled. The differential diagnosis includes Fanconi anemia, Holt-Oram syndrome, and Roberts syndrome. Management consist of platelet transfusions at a threshold of less than 10,000/µL. Adaptive devices are generally preferred to prosthetics for upper limb deformities.

REFERENCES:

  1. Toriello HV. Thrombocytopenia-absent radius syndrome. Semin Thromb Hemost. 2011;37(6):707-712. doi:10.1055/s-0031-1291381
  2. Klopocki E, Schulze H, Strauss G, et al. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia–absent radius syndrome. Am J Hum Genet. 2007;80(2):232-240. doi:10.1086/510919
  3. Albers CA, Paul DS, Schulze H, et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012;44(4):435-439. doi:10.1038/ng.1083
  4. Parikh TB, Udani RH, Nanavati RN, V BR. Fanconi’s anemia in newborn. Indian Pediatr. 2005;42(3):285-287. Accessed April 28, 2020. http://www.indianpediatrics.net/mar2005/mar-285-287.htm
  5. Albers CA, Newbury-Ecob R, Ouwehand WH, Ghevaert C. New insights into the genetic basis of TAR (thrombocytopenia-absent radii) syndrome. Curr Opin Genet Dev. 2013;23(3):316-323. doi:10.1016/j.gde.2013.02.015
  6. Greenhalgh KL, Howell RT, Bottani A, et al. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002;39(12):876-881. doi:10.1136/jmg.39.12.876
  7. Tongsong T, Sirichotiyakul S, Chanprapaph P. Prenatal diagnosis of thrombocytopenia-absent-radius (TAR) syndrome. Ultrasound Obstet Gynecol. 2000;15(3):256-258. doi:10.1046/j.1469-0705.2000.00047.x
  8. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program. 2007;29-39. doi:10.1182/asheducation-2007.1.29
  9. Thrombocytopenia-absent radius syndrome. Genetics Home Reference. Reviewed February 2017. Accessed April 28, 2020. https://ghr.nlm.nih.gov/condition/thrombocytopenia-absent-radius-syndrome
  10. Toriello HV. Thrombocytopenia absent radius syndrome. GeneReviews. Published December 8, 2009. Updated December 8, 2016. Accessed April 28, 2020. https://www.ncbi.nlm.nih.gov/books/NBK23758/
  11. Ballmaier M, Schulze H, Strauss G, et al. Thrombopoietin in patients with congenital thrombocytopenia and absent radii: elevated serum levels, normal receptor expression, but defective reactivity to thrombopoietin. Blood. 1997;90(2):612-619.
  12. Geddis AE. Inherited thrombocytopenia: Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Semin Hematol. 2006;43(3):196-203. doi:10.1053/j.seminhematol.2006.04.003
  13. McLaurin TM, Bukrey CD, Lovett RJ, Mochel DM. Management of thrombocytopenia-absent radius (TAR) syndrome. J Pediatr Orthop. 1999;19(3):289-296.