Tar Syndrome

 

Prof. Jennette Mol P James

 

ABSTRACT:

Thrombocytopenia absent radius (TAR) syndrome is a very rare and infrequently seen congenital disorder with an approximate frequency of 0.42/100,000 live births. It is associated with bilateral absence of radii, hypo-megakaryocytic thrombocytopenia, and presence of both thumbs. The other systems which are affected by TAR syndrome include skeletal, hematologic, and cardiac systems. Intracranial hemorrhages due to thrombocytopenia and cardiac disorders are a common association usually seen with this syndrome and are usual cause of death. We describe a 3-month-old infant who was diagnosed with TAR syndrome on the basis of clinical features (thrombocytopenia and bilateral absent radius bone and confirmed by genetic analysis). The patient was diagnosed to have Tetralogy of Fallot, for which the infant was managed with definitive repair and thrombocytopenia was managed with platelet transfusion. Infants with TAR syndrome should be assessed for other associated malformations of various systems and followed up regularly and parents should be counseled for associated expected complications in these patients. We report an infant with TAR syndrome with Tetralogy of Fallot, which has not been reported in medical literature until now and this is the first case of its type.

 

 

 

INTRODUCTION:

A nine year child got admitted to the pediatric ward with the complaints of fatigue, decreased food intake, episodes of bleeding from mouth and slow growth rate.

 

Significant Physical examination findings:

·       General appearance-small for age stature, hyper pigmentation of the skin, small head, presence of plaque on teeth and brownish in color.

·       Absence of radial bone on hands, supernumerary thumb, surgical incision mark on the right wrist, week muscles.

 

Past medical/surgical history:

·       During the sixth month intranatal scan, growth retardation was identified. Birth weight was 2 kg, had physiological jaundice and underwent phototherapy.

·       Absence of radius on both hands. Supernumerary thumb.

·       Muscles weaker, Unable to dress up self, feed, or brush independently.

·       At the age of one year underwent open reduction and internal fixation on the right wrist for the correction of clubbed wrist joint.

 

Nutritional status:

·       Habit of Less food intake, allergic to milk. Body weight is 10 kg (expected weight is 26kg.According to IAP classification severe malnutrition).

·       Reported milk allergy.

·       Anemia.

 

INVESTIGATIONS:

CBC-Hb-7.1gm

RBC-2.5ml/cum

PCV-19%

 

PLATELET-4,000cell/cum

USG-small left kidney

 

BONE MARROW MICROSCOPY:

Mildly hypo echoic liver parenchyma.

Hypo cellular marrow, pancytopenia, and possibility of aplastic anaemia.

 

PERIPHERAL BLOOD SMEAR:

Fanconis anemia in view of Growth retardation supernumerary thumb and mildly increased Hbf.

 

And the pediatrician diagnosed her condition as TAR SYNDROME

 

TAR SYNDROME:

TAR Syndrome (Thrombocytopenia with absent radius is a rare genetic disorder that is characterized by the absence of the radius bone (radial aplasia) in the forearm and a dramatically reduced platelet count.

 

Infant with thrombocytopenia-absent radius syndrome. The arms and forearms are shortened, with radial deviation of both hands because of the absence of bilateral radii. The legs are normal.

 

TAR syndrome is characterized by the absence of a bone called the radius in each forearm, short stature, and thrombocytopenia. The thrombocytopenia often appears first in infancy but becomes less severe or returns to normal over time. Infants and young children are particularly vulnerable to episodes of severe bleeding which may occur in the brain and other organs. Children who survive this period and do not have damaging bleeding in the brain usually have a normal life expectancy and normal intellectual development. Other signs and symptoms vary but may include heart defects, kidney defects, and other skeletal abnormalities. About half of people with TAR syndrome also have difficulty digesting cow's milk. TAR syndrome is thought be caused by a deletion of genes on chromosome 1q21.1 in concert with another genetic change that has yet to be identified.

HISTORY:

In 1929 Greenwald and Sherman described the first patient with TAR syndrome. An autosomal recessive inheritance pattern was proposed because TAR affected more than one member of some families. In 1988 Hedberg published an article with 100 cases.

 

Definition:

Thrombocytopenia-absent radius (TAR) syndrome is a very rare congenital malformation syndrome characterized by bilateral radial aplasia and thrombocytopenia.

 

Age:

TAR syndrome is congenital, and patients usually present with symptomatic thrombocytopenia in the first week of life.

Sex:-the male to female ratio is 1:1

 

Epidemiology:

The incidence is 0.42 per 100,000 live births (international)

 

Causes:

Mutations in the RBM8A gene cause TAR syndrome .the RBM8A gene provide instructions for making a protein called RNA-binding motif protein 8 A .This proteins is believed to be involved in several important cellular functions involving the production of other proteins.

 

The affected individual usually inherits An the RBM8A mutation from one parent. In about 75% of cases, the affected person inherits a copy of chromosome 1 with the 200-kb deletion from the other parent. In the remaining cases the deletion occurs during the formation of reproductive cells (eggs and sperm) or in early foetal development. Although parents of an individual with TAR syndrome can carry an RBM8A mutation or a 200-kb deletion, they typically do not show signs and symptoms of the condition.

 

Pathophysiology:

Thrombocytopenia absent radius (TAR) is a rare syndrome associated with bilateral absence of radii, hypo-megakaryocytic thrombocytopenia, and presence of both thumbs.¹ TAR syndrome abnormalities include various systems, including skeletal, hematologic, and cardiac system abnormalities. This association of simultaneous involvement of various systems has been postulated due to the simultaneous development of the heart, radii, and megakaryocytic at 6–8 weeks’ gestation. The similarity of tar syndrome to congenital rubella suggests intrauterine injury when the involved systems develop, but a common etiologic agent has not been identified.

 

The platelet abnormality reflects platelet hypoproductivty, for which numerous explanatory theories have been proposed. Simulators of megakaryocytopoises (eg.thrombopoietin) are responsible for inhibiting platelet production.

 

Thrombocytopenia prevents normal blood clotting, resulting in easy bruising and frequent nose bleeds. Hemorrhages can damage the brain and lead to intellectual disability. Affected children who survive this period and do not have damaging hemorrhages in the brain usually have a normal life expectancy and normal intellectual development.

 

The severity of skeletal problems in TAR syndrome varies among affected individuals. The radius which is the born on the thumb side of the palm is almost always missing in both arms. The other bone in the forearm which is called the ulna is sometimes under developed or absent in one or both arms.

 

Mortality and morbidity:

The major cause of mortality in TAR syndrome is hemorrhage. The incidence of hemorrhage is limited to the first 14 months of life. In a study by Hedberg and associates 18 of 20 deaths in 76 patients were due to hemorrhagic events, most of patients who died had platelet counts<10x10⁹/L.

 

Bleeding and hemorrhage can also result in clinically significant morbidity, especially intracranial hemorrhage. Hand and upper extremity function is usually good if radial aplasia is the only skeletal abnormality. However, patients require plastic surgery, occupational therapy, and physiotherapy.

 

Symptoms:

About 50% of affected infants are symptomatic in the first week of life; and 90% are symptomatic by the age of 4 months. Thrombocytopenia can fluctuate over time, with increasing age the occurrence of thrombocytopenic episodes decreases. Thrombocytopenia can improve to a near normal state. On specific stress, infection and diet (allergy to cow’s milk) may precipitate episodes. Symptoms include purpura, peteciae, epitaxis, Melina, hemoptysis, hematuria, hemetemesis and rarely intracranial hemorrhage.

 

Symptomatic cow’s milk allergy is associated with 47% of all cases of TAR syndrome and patients may present vomiting, bloody diarrhea and failure to thrive. In 7% of cases mental retardation occurs due to intracranial hemorrhage.

 

Upper extremity abnormalities range from isolated absent Radii to phocomelia. Abnormalities include the following:

·       Bilateral radial aplasia

·       Radial club hand.

·       Hypo plastic carpals and phalanges.

·       Hypo plastic ulnae, humeri ad shoulder girdles.

·       Syndactly and clinodactly of fingers and toes.

·       Altered palmar contours.

·       Severe ulnar and humeral shortening phocomedia

·       Cardiac anomalies occur in 15-33% of Asians.

·       Facial anomalies in 53% of patients. E.g.: Micrognathia, toll broad foreheads.

·       Short stature (95% patients are at or below 50^th percentile)

·       Skeletal malformations.

·       Thumbs are hypo plastic or absent in patients with fanconi anemia and radial defects.

 

The manifestation of TAR and Fanconi anemia frequently overlap. In faconi anemia thrombocytopenia is rarely present at birth; it develops later on in child-hood or even in adult-hood.

 

Investigations:

·         The platelet count is frequently less than 50x 10⁹/L (15-30 x 10⁹/L)

·         Platelet morphology looks normal on blood smear examination.

·         Eosinophilia is observed in 50% of patients.

·         Leukocytosis may be present with WBC count > 35x 10⁹/L with a left shift and picture of leukomold reaction.

·         Anemia may be present secondary to bleeding.

 

Imaging Studies:

·       Characteristic skeletal involvement (i.e., absent radii) is detectable during pre-natal transvaginal ultrasonography as early as 13 weeks gestation. When sufficient fetal skeletal ossification is present.

·       Upper limb abnormalities on prenatal sonograms suggest numerous syndromes in the differential diagnosis.

·       After radial aplasia is observed ultrasonography of the extremities, face and kidneys are indicated.

 

Treatment:

·         Avoidance of trauma, avoidance of anti platelet drugs (e.g.: aspirin, NSAIDs), avoid prolonged pressure on the injection site.

·         First aid for visible acute hemorrhage- applies firm steady pressure on the site of bleeding.

·         Keep the patient warm, elevate the bleeding limb.

·         Hospitals stay for supportive care like platelet transfusion.

·         Spleenectomy may partially effective for the treatment of thrombocytopenia in adults.

·         Hematopoietic stem cell transplantation is an option for patients who remain thrombocytopenic with bleeding despite platelet transfusion.

 

Surgical Carte:

·         Splinting of the hands (and legs if indicated) during infancy improves future function

·         Surgical correction of the arm deformity.

·         Use of adaptive devices.

 

Diet:

·         Patient should avoid ingesting cow-milk for the first year of life because cow-milk allergy is associated with TAR and may precipitate thrombocytopenic episodes.

·         Blood in the stool is reported in 20% of patients. Removal of milk from the diet alleviates this symptom.

 

Activity:

·         Careful handling of the patient with padding of his or her crib and application of soft helmet can be used in the first year of life. Most patients are adequately hemo-static after the first year of life to allow them to perform normal activities. Patients should avoid trauma (e.g.: contact sports) during periods of thrombocytopenia.

 

A study by Al Kaissi et al indicated that optimal treatment of TAR can allow patients to participate in most activities of daily living, albeit with some ulnar deviation and with limitations of wrist extension and on total active range of digital motion. The study included five patients in whom the wrist underwent realignment and stabilization and whose ulnar forearm bows were reversed through rebalancing of the musculo tendinous forces around the wrist.

 

Prognosis:-Limitation is not the end…life is ahead..

 

The first two years of life are most critical in TAR syndrome. During this time, children frequently develop life-threatening bleeding episodes due to extremely

 

Low platelet levels (thrombocytopenia).these episodes decrease with age and platelet counts are usually normal by the time a child goes to school. Many individuals with TAR syndrome are allergetic to cow milk, which can also exacerbate the symptoms of thrombocytopenia. Intellectual development is usually not affected by TAR syndrome, though some children have intellectual disability due to complications from bleeding within the brain. People with TAR syndrome may be at increased risk of developing acute leukemia during childhood or adulthood.

 

CONCLUSION:

TAR is a rare syndrome and is associated with bilateral absence of radii, hypo-megakaryocytic thrombocytopenia, and presence of both thumbs. TAR syndrome abnormalities include various systems including skeletal, hematologic, and cardiac system abnormalities. Babies with suspected TAR syndrome should be assessed for other associated malformations of various systems like renal malformations, cardiac defects like atrial septal defects, VSD, and very rarely Tetra logy of Fallot, facial dysmorphism, short stature, macrocephaly, capillary hemangioma, and hematological malignancies in later life, requiring regular follow-up. Antenatal diagnosis of TAR syndrome is possible in the first trimester but that requires thorough antenatal checkup and regular follow-up. The risk of bleeding is highest during the first 2 years of life span after which the platelet count may improve. Close surveillance for thrombocytopenia with regular follow-ups and platelet transfusion to raise platelet count above 40,000/mm³ are the mainstay of treatment. Treatment of associated deformities requires a multidisciplinary approach that contributes to the successful management of such case.

 

REFERENCES:

1.      Kliegman et al. Nelson Textbook of Paediatrics.vol 2,18th edition. New Delhi: Elsevier publications; 2008, pg.2085-2087.

2.      Parthasarathy etal. IAP Text book of Paediatrics.Fourth edition. New Delhi: Jaypee Publications; 2010.pg .1267-1269.

3.      Paul K Vinod, Bagga Arvind.Gai essential paediatrics. eigth edition.CBS publications; New Delhi: 2009.pg. 349-351.4. Wong’s nursing Care of Infants and Children.eigth edition. New Delhi: Elsevier Publication; 2007. pg.1252-1253.

4.      medscape.com/article/959262-overview

5.      https://en.wikipedia.org/wiki/TAR_syndrome

6.      https://health.info.com/serp?q=tar%20syndrome

7.      https://healthjade.com/tar-syndrome

8.      www.nicklauschildrens.org › conditions › thrombocytopenia.

 

 

Received on 30.07.2020         Modified on 29.08.2020

Accepted on 25.09.2020      ©A&V Publications All right reserved