Familial thrombocythemia: A case report of three Arab siblings with MPL gene mutation p. Pro106Leu and abnormal platelet aggregation studies

Background: Familial thrombocythemia is a rare chronic myeloproliferative disorder caused by molecular alterations in the thrombopoietin gene (THPO) or in the gene for the thrombopoietin receptor (MPL). Activating mutations in THPO induces megakaryocytopoiesis due to increased thrombopoietin (TPO) production.Three germ line mutations in MPL causing thrombocytosis have been described;1. p.Ser505Asn-associated with autosomal-dominant thrombocytosis.2. p.Lys39Asn-a functional polymorphism found restricted to African Americans.3. p.Pro106Leu-frequently found in ArabsThe mutation p.Pro106Leu is thought to be inherited in an autosomal recessive manner. It involves extracellular domain of MPL gene affecting its binding ability to TPO thus reducing its clearance and inducing thrombocytosis.Objectives: To highlight clinical features and management of patients with MPL Pro106Leu mutations.Design/Method: Case report and literature review.Results: Three of five siblings (ages 14, 10, 2 yrs) from a consanguineous Middle Eastern family were evaluated for persistent high platelet count (705,000–991,000/microlitre). Older two siblings had history of epistaxis, easy bruisability and prolonged bleeding with minor surgical procedures such as dental extractions and polypectomies. No thrombotic events were noted. Extensive work up for thrombocytosis was negative except for sequencing of MPL gene which revealed homozygosity for p.Pro106Leu (c.317C \u3e T) mutation in all three patients. Both parents and the two other siblings (brother and sister) were found to be heterozygous carriers and had normal platelet counts. Global platelet aggregation abnormalities were present in all siblings (with high dose ADP, arachidonate, low dose collagen, epinephrine). The eldest sibling underwent dental extraction and good hemostasis was achieved with desmopressin (DDAVP). Prior to the procedure he underwent a DDAVP trial which showed a partial correction of the platelet aggregation studies.Conclusion: Our cases highlight the importance of considering MPL mutations in patients of Arab descent presenting with thrombocytosis and abnormal platelet aggregation studies given the high rate of consanguinity and carrier rate of 6%. Patients with the MPL Pro106Leu mutations have a predisposition for bleeding diathesis rather than thrombotic events and identification of this mutation may help in clinical management. Larger ethnic specific trials may be needed to understand the pathophysiology of platelet dysfunction associated with this mutation

Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome

The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation

Case Report Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome

The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation

Hemoglobin Sunshine Seth: A Case Report of Low-Oxygen-Affinity Hemoglobinopathy

Pulse oximetry is routinely used in the newborn nursery for clinical monitoring and to detect critical congenital heart disease. The differential diagnoses for reduced peripheral oxygen saturation in an infant include congenital heart disease, respiratory distress syndrome, transient tachypnea of the newborn, persistent pulmonary hypertension of the newborn, meconium aspiration syndrome, pneumonia, pneumothorax, and sepsis. The diagnostic evaluation for neonatal hypoxemia can be invasive and expensive. When this evaluation is unrevealing, other interventions may be tried without clear benefit to the patient, including, but not limited to, supplemental oxygen. Therefore, it is important to consider alternative, albeit rare, diagnoses, including hemoglobinopathies with abnormal oxygen binding properties. Mutations in the structure of alpha- and beta-globin chains can alter the affinity of hemoglobin for oxygen, and changes in oxygen affinity may result in changes in the oxygen saturation detected by pulse oximetry. These changes may or may not be of clinical significance. This case report describes Hemoglobin Sunshine Seth, a rare low-oxygen-affinity hemoglobin variant presenting as reduced peripheral oxygen saturation in an otherwise well-appearing infant male

Empiric treatment of protracted idiopathic purpura fulminans in an infant: a case report and review of the literature

Abstract Introduction Idiopathic purpura fulminans is a cutaneous thrombotic disorder usually caused by autoimmune-mediated protein C or S deficiency. This disorder typically presents with purpura and petechiae that eventually slowly or rapidly coalesce into extensive, necrotic eschars on the extremities. We present the first known case of idiopathic purpura fulminans consistent with prior clinical presentations in the setting of a prothrombotic genetic mutation, but without hallmark biochemical evidence of protein C or protein S deficiency. Another novel feature of our patient's presentation is that discontinuation of anti-coagulation has invariably led to recurrence and formation of new lesions, which is unexpected in idiopathic purpura fulminans because clearance of autoimmune factors should be followed by restoration of anti-coagulant function. Although this disease is rare, infants with suspected idiopathic purpura fulminans should be rapidly diagnosed and immediately anti-coagulated to prevent adverse catastrophic outcomes such as amputation and significant developmental delay. Case presentation A six-month-old Caucasian boy was brought to our pediatric hospital service with a low-grade fever and subacute, symmetric, serpiginous, stellate, necrotic eschars on his forearms, legs and feet that eventually spread non-contiguously to his toes, thighs and buttocks. In contrast to his impressive clinical presentation, his serologic evaluation was normal, and he was not responsive to corticosteroids and antibiotics. Full-thickness skin biopsies revealed dermal vessel thrombosis, leading to a diagnosis of idiopathic purpura fulminans and successful treatment with low-molecular-weight heparin, which was transitioned to warfarin. Long-term management has included chronic anti-coagulation because of recurrence of lesions with discontinuation of treatment. Conclusion In infants with necrotic eschars, it is important to first consider infectious, inflammatory and hematologic etiologies. In the absence of etiology for protracted idiopathic purpura fulminans, management should include tissue biopsy, in which thrombotic findings warrant a trial of empiric anti-coagulation. Some infants, including our patient, may need long-term anti-coagulation, especially when the underlying etiology of coagulation remains unidentified and symptoms recur when treatment is halted. Given that our patient still requires anti-coagulation, he may have a yet to be identified autoimmune-mediated mechanism for his truly idiopathic case of protracted purpura fulminans.</p

Delayed methotrexate clearance despite carboxypeptidase-G2 (Glucarpidase) administration in 2 patients with toxic methotrexate levels

High-dose methotrexate has been a treatment for osteosarcoma; however, its nephrotoxic effects are considerable. Carboxypeptidase-G2 (glucarpidase) was approved by the US Food and Drug Administration in 2012 for treatment of toxic methotrexate levels. We report our experience using glucarpidase under compassionate use before Food and Drug Administration approval in 2 patients who had delayed methotrexate clearance and prolonged kidney injury despite glucarpidase administration. Our results show that patients with methotrexate toxicity may require repeated doses of glucarpidase in addition to supportive measures, such as dialysis