Thrombocytopenia with Absent Radii Syndrome TAR,Fanconi's Anemia

4th Pediatric Infectious Diseases Conference

ISSN 0973 - 0958

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NEONATAL THROMBOCYTOPENIA - A CHALLENGE

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Neonatal Thrombocytopenia in newborns

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thrombocytopenia due to maternal idiopathic thrombocytopenia

Congenital Amegakaryocytic Thrombocytopenia

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Dr.M.R.Lokeshwar, Dr.Manisha Bavdekar, Dr.
Shilpa Kulkarni, Dr. Nitin Shah

Thrombocytopenia with Absent Radii syndrome (TAR) :

Thrombocytopenia with absent radius (TAR) is a congenital syndrome characterized by severe thrombocytopenia with bilateral absent radii and may be associated with other skeletal abnormalities (57). By now more than 100 cases have been reported in the literature (58,59,60). Other skeletal abnormalities are usually present. Limbs are more involved than the trunk. Hypoplasia, aplasia or malformation of ulna seen in 78% of cases, hand 75% and humerus 40% cases. However, thumbs and digits are almost always present which distinguishes TAR from Fanconi's anemia (60,61). It may be associated with congenital heart defect like tetralogy of fallot and ASD present in 1/3rd of cases (57). Pregnancies are usually uncomplicated and there is no maternal history of exposure to drug, radiation and environment. It is transmitted in an autosomal recessive fashion, and consanguinity is not a feature (60).

Various mechanisms responsible for thrombocytopenia includes :

Decreased platelet production as a consequence of reduced megakaryocytes in the marrow.
Impaired platelet production from the megakaryocytes.
These patients have elevated concentration of thrombopoietin (TPO) and TPO receptors on the surface of the platelet. However, platelet induced tyrosine phosphorylation of platelet protein is completely absent or markedly reduced suggesting lack of response to TPO in signal transduction, pathway of its receptors (u-PL) (68,69).

Sekine and colleagues (69) could grow megakaryocytic colonies from patients with TAR syndrome in the presence of TPO. However, colonies grown appeared smaller suggesting decreased proliferative response to TPO.

Bleeding manifestation and severe thrombocytopenia, platelet count less than 10-30,000/uL have been reported in more than 50% of cases at birth or before the age of 1 week and 90% of patients by 4 months age (60). Approximately 25% of affected individuals die due to intracranial hemorrhage (ICH) (56). If they survive through this period, the thrombocytopenia generally resolves over a period, and normal platelet count is usually achieved by school age (64). First year of life is period of high risk and over 90% of death from hemorrhage occurs during this time, over 40% death occur in first 4 months of life (60).

Other hematologic abnormalities include leukemoid reactions with white cell count of 100,000 or more seen in 63% cases, eosinophilia, anemia secondary to iron deficiency. Bone marrow examination reveals absent or reduced or immature hypoplastic megakaryocytes. Bone marrow cellularity are normal with normal or increased myeloid and erythroid series (56, 57). Results of platelet function tests are variable and are difficult to interpret in thrombocytopenic individuals (65).

Evaluation of therapeutic intervention is difficult in view of spontaneous remission and exacerbation of thrombocytopenia. Corticosteroids have been tried with beneficial results (60). Judicious use of platelet transfusion given particularly during acute bleeding episode or prophylactically before surgery is treatment of choice. Most children tolerate orthopedic procedures well. Prenatal diagnosis of TAR by demonstration of absent radii using fetal radiography at 16-20 weeks has been reported.

Prognosis depends upon the severity and duration of thrombocytopenia with overall mortality of 40% (60). Children who survive do not appear to be at increased risk for developing leukemia or aplastic anemia.

Fanconi's Anemia (FA) :

Fanconi's anemia (FA) is familial aplastic anemia associated with number of congenital anomalies and inherited by autosomal recessive pattern (57). Usually presents during middle childhood (4-11 years) and is characterized by progressive persistent anemia, skeletal anomalies with absent or hypo-plastic or bifid thumb (66%), abnormal skin pigmentation (64-77%), microcephaly (25-40%), renal anomalies (34-40%), hypogonadism, growth retardation, short stature and mental subnormalities. Since Fanconi's description of three brothers with pancytopenia and physical anomalies in 1927, (56) more than 700 cases have been reported. Pancytopenia usually does not manifest until childhood (median age 7 yrs). These children rarely experience hemato-logical problems in the neonatal period (77, 71, 73, 74).

Diagnosis of Fanconi's anemia is based on clinical features along with pancytopenia on the peripheral smear and the presence of chromosomal abnormalities, breaks, gaps, rearrangements and exchanges and Endo-reduplications in base line culture and more so when clastogenic agents like diepoxybutane used (75, 76, 77).

Ultrasound abdomen or intravenous pyelography may reveal kidney anomalies like horse shoe kidney, double ureter, bifid pelvis, ectopic kidney etc.

Fetal characteristics of RBC is demonstrated by macrocytosis, increased fetal hemoglobin and increased i antigen (72,74). 25% of affected individuals may be structurally normal and may not have dysmorphic features (57).

Treatment of this condition includes androgen therapy, bone marrow transplantation (78), and regular supportive therapy with packed red cell blood transfusion (56, 61, 71, 72), Butterini et al (77) reported 388 patients with Fanconi's anemia and 35% of these patients died at the median age of 13 years. They may develop leukemia - myeloid leukemia or myelodysplastic syndrome, other malignancies and hepatic disease (66,72). Several reports of successful umbilical cord blood derived stem cell transplantation from histocompatible siblings is the new therapeutic alternative. Recombinant hematopoietic growth factors also have been tried (77)

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