Ehlers-danlos syndrome with platelet aggregation defect-presenting as mysterious bleeding disorder

Introduction

Ehlers-Danlos syndrome (EDS) is a heritable group of generalized disorder of connective tissue characterized by fragility of skin and blood vessels, hyperextensibility of the skin and joint hypermobility. The diagnosis is mainly clinical. Milder variants of the classical mitis form of the Ehlers-Danlos syndrome are common in the population and can be identified by well defined clinical scoring system.[1],[2] The identification of the syndrome is important in the clinical settings like undiagnosed cases of bleeding diathesis, cases of recurrent dislocations, rupture of hollow viscus and also for prognostication of outcome of scar after cutaneous surgery. At least ten clinical types of EDS from type I to type X have been described with variable inheritance like AD, AR and XLR. Type X EDS inherited as an autosomal recessive disorder is characterized by clinical features similar to EDS II (mitis) variety associated with defect of platelet aggregation due to fibronectin deficiency.3 We describe here one such case, which presented with recurrent episodes of epistaxis, purpura and ecchymoses and was also found to have defect of platelet aggregation. The only other sibling was also mildly affected with recurrent episodes of mild epistaxis.

Case Report

A seven-year-old girl resident of Orissa, was referred to us by the paediatricians for investigation of multiple nodular swellings over joint surfaces present since last six months. Prior to this, there was history of petechiae following a febrile illness with diarrhea at the age of six months requiring blood transfusion in a hospital at Bikaner. She was later investigated in a Military Hospital at Delhi, which included bone marrow examination, and was diagnosed erroneously as idiopathic thrombocytopenic purpura. At the age of two years, she had a second episode of purpura along with epistaxis and malena again requiring repeated blood transfusions at a Military Hospital in Calcutta. After detailed investigations possibility of ITP was still entertained and the child was discharged. Between two to five years of age she had minor episodes of epistaxis, petechiae and ecchymosis not requiring hospitalization. At the age of five years she had massive epistaxis and the haemoglobin fell to 2.0 gm/dl again requiring repeated blood transfusions. At this point of time it was suspected that the child was not having ITP. Since she was having massive bleeds in spite of normal platelet counts. She was transferred to Military Hospital at Pune for further investigations in Feb.′99. Bone marrow examinations revealed normal number of platelets and a picture of megaloblastic anaemia most likely post transfusion. Platelet function studies showed defect of aggregation of platelets to epinephrine, ADP, collegen and ristocetin. With the possibility of Glanzmann′s disorder, she was referred to Institute of Immune-haematology at Mumbai for further studies. Demonstration of glycoproteins IIB and IIIA ruled out this possibility. PT and APT were normal and factor VIIIC activity was 100% (normal 50-150%), ruling out the possibility of von-Willebrand′s disease. Total platelet IgG was 27 ng/106 platelets (normal 1.6-18ng/106 platelets). With the results of the investigations still inconclusive, she was discharged as a case of anaemia with platelet dysfunction. There was no history of any drug intake prior to each episode of purpura, no history of increased bleeding from wounds or after dental extraction, no history of seizures, heamaturia, heamatochaesia or heamarthrosis.

She was product of 1° consanguineous marriage of normal parents. However, the younger sibling, five-year-old boy also had history of repeated mild to moderate epistaxis on an average once a month for the last three years.

Clinically general, systemic and ophthalmic examination was normal. Dermatological examination revealed firm to hard, nontender nodules, 1-3 cm in diameter present over both wrists, both shoulders, right index finger and dorsum of right foot. Spontaneous bruises appeared over right forearm on 1st June 2001 and over left thigh on 21st June 2001. Skin was mildly hyperextensible, especially over abdomen. Joint hypermobility of fingers, wrists, elbows, knees and spine was demonstrable. Gorlin′s sign was negative. Atrophic scars were present over right knee. Using the criteria as described by Holzberg M et al[1], she had a score of 9/20, thus fulfilling the criteria for diagnosis of EDS. Similarly, the younger sibling scored 5/20 again fulfilling the criteria of EDS. Both the parents scored 0/20.

Investigations done showed haemoglobin to be 12.8gm%, with a normal hematocrit, RBCs, MCV, MCHC, MCH, reticulocyte count and PBS. Platelet count was 3,60,000/cmm. X-ray wrists showed soft tissue swellings over both wrists and osteopenic bones. 2D echo did not reveal any mitral valve prolapse and ANA was negative. Biopsy from the nodule revealed histopathological features consistent with molluscoid tumours of EDS. Special stains viz. Verhoeff-van Gieson and Masson trichrome stain revealed thick irregular collagen in the dermis along with laying down of elastic fibers replacing collagen in certain areas of dermis. Electron microscopic studies in proposita, her younger sibling and father to ADP, epinephrine and collagen were normal.

She was diagnosed as a case of autosomal recessive inherited milder form of EDS with platelet aggregation defect most probably EDS type X with a mildly affected younger sibling.

Discussion

A seven-year-old girl with history of repeated episodes of spontaneous bleeding in the skin and from the nose, with onset at the age of six months, was no doubt suffering from a defect of haemostasis. Initial diagnosis of ITP in the absence of significant thrombocytopenia was not justifiable. However, the child was managed with blood transfusions of fresh blood with improvement each time. With the screening tests for clotting defect being normal, we were left with only two possibilities i.e. defects of platelet function and vascular defect. When she presented at the age of five-year with massive epistaxis, she was rightly suspected to be suffering from a defect other than ITP. She was investigated at Armed forces medical College, Pune and detected to have platelet aggregation defect to agonists ADP, epinephrine, collagen and ristocetin. Abnormal aggregation of platelets to agonists other than ristocetin and absence of giant platelets in the smear ruled out Bernard-Soulier syndrome. Similarly under the same laboratory settings and with normal factor VIII-C activity ruled out von-Willebrand′s disease. Abnormal aggregation to ristocetin ruled out the possibility of storage pool disease. With demonstration of glycoprotein IIB and IIIA, Glanzmann′s disease was also ruled out. This only suggested that she was suffering from a rare cause of platelet dysfunction.

Only when she presented to the dermatologist with nodular swellings (later diagnosed histopathologically as molluscoid tumours), was hereditary vascular defect as a cause of bleeding diathesis suspected. In the absence of gross clinical features of EDS, clinical scoring system as defined by Holzberg M et al[1], was used to diagnose it as a case of EDS with clinical features resembling EDS II (mitis) variety. Skin histopathology and ultrastructure studies supported this diagnosis with demonstration of thick, irregular collagen fibrils.

EDS clinically resembling type II (mitis) variety with autosomal recessive inheritance, defects of platelet aggregation and demonstration of thick irregular collagen fibrils conforms to EDS X (fibronectin defect) as described by Arneson MA et al.[3] Only one family with this defect has been described so far. Fibronectin, an adhesive glycoprotein, found in insoluble form in connective tissue is important for cross-linking of collage. Present in soluble form in plasma, it helps in platelet adhesion and stimulates their aggregation. Addition of fibronectin to plasma of the affected kindred corrected their platelet aggregation defect. Most of these hereditary platelet function defects improve with age.[4] This may be the reason for normal platelet function in our patient at the age of seven years and also no episodes of epistaxis for the last two years.

Anstey A et al[5] reviewed all the cases of EDS reported with defects of platelet function and coagulation defects. In their own series of 51 patients of EDS, only 18% were found to have such defects and in the rest the cause of easy bruisability was only due to defect of structural integrity of skin and blood vessels. The most recently described case of EDS with platelet function defect is by Espa-nol I et al.6 In their patient the cause for platelet dysfunction was due to partial delta-storage pool disease and the abnormality could be corrected by addition of desmopressin acetate-DDAVP.