Treatment of transfusion-dependent congenital dyserythropoietic anemia Type I patients with pegylated interferon alpha-2a.

OBJECTIVE: Pegylated IFN-α2a has been reported in two case reports as being efficacious in treating CDA-I patients. This study aims to assess its efficacy on a series of CDA-I patients. METHODS: Study sample consisted of seven CDA type 1 transfusion-dependent patients. They received pegylated interferon alpha-2a at an initial dose of 90-180 µg once a week, tapered according to clinical response and side effects. Good response was defined as Hb ≥ 10 g/dL for ≥3 months, partial response was defined as 7 ≤ Hb<10 g/dL for ≥3 months, and no response was defined as HB < 7 g/dL for over 3 months on treatment. Time to response was defined as the time needed to achieve hemoglobin levels ≥ 10 g/dL without transfusion. Patients were evaluated periodically by abdominal ultrasounds to rule out liver adenomas. RESULTS: Five patients (71%) had a good response to treatment. One patient stopped treatment due to side effects. One patient had partial response. One patient, with more severe phenotype and poor compliance, had poor response to treatment. No abnormal findings were found in ultrasound examination. No effect on serum ferritin level could be established. CONCLUSION: Pegylated interferon α2a therapy is efficacious in CDA-I patients with a reasonable safety profile.

An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.

Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.

Autoinflammatory bone disorders: update on immunologic abnormalities and clues about possible triggers.

PURPOSE OF REVIEW: To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the monogenic forms of the disease. RECENT FINDINGS: Ongoing research in murine, canine and human models of sterile bone inflammation has solidified the hypothesis that sterile bone inflammation can be genetically driven. Mutations in Pstpip2, LPIN2 and IL1RN have been identified in monogenic autoinflammatory bone disorders that have allowed more detailed dissection of the immunologic defects that can produce sterile osteomyelitis. Recent studies in murine chronic multifocal osteomyelitis, deficiency of the interleukin-1 receptor antagonist (DIRA), Majeed syndrome and SAPHO syndrome reveal abnormalities in innate immune system function. IL-1 pathway dysregulation is present in several of these disorders and blocking IL-1 therapeutically has resulted in control of disease in DIRA, Majeed syndrome and in some cases of SAPHO and CRMO. Basic research demonstrates the importance of the innate immune system in disease pathogenesis and offers clues about potential disease triggers. SUMMARY: Research and clinical data produced over the last several years support the important role of innate immunity in sterile osteomyelitis. Based on what has been learned in the monogenic autoinflammatory bone disorders, IL-1 is emerging as an important pathway in the development of sterile bone inflammation.

Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.

Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

Clinical care of children with sterile bone inflammation.

PURPOSE OF REVIEW: To review the current literature of sterile bone inflammation in childhood and to evaluate the evidence for clinical care including diagnostic methods and treatment. RECENT FINDINGS: Chronic noninfectious osteomyelitis includes several different entities marked by sterile bone inflammation associated with histologic evidence of a predominant neutrophil infiltration in the absence of autoantibodies and autoreactive T cells, some of which are associated with a genetic mutation. Whole body MRI is helpful in detecting asymptomatic lesions. Initial treatment with NSAIDs is usually sufficient to control symptoms as the bone heals. However, if the lesions persist and do not respond to first-line treatment, or involve the spine or hip, treatment with bisphosphonate will usually lead to a resolution of symptoms. Rarely, treatment with anti-TNF agents is required. SUMMARY: This review summarizes recent information on diagnosis, treatment and prognosis of disorders involving sterile bone inflammation in childhood. It also addresses the evolving differential diagnosis for autoinflammatory disorders that include sterile bone inflammation and presents a treatment algorithm for management.

Dyserythropoiesis in 105 patients with visceral leishmaniasis.

Hematologists in the developing world are increasingly involved in diagnosing parasitic diseases that involve the bone marrow. With a worldwide annual incidence of half a million cases and 12 million infected people, visceral leishmaniasis is one such serious disease. It mainly affects malnourishedand economically underprivileged children. Recently, this disease has been seen in acquired immunodeficiency syndrome patients and in travelers to endemic areas. Over an 18-year period, 442 marrow examination requests were received by our department, and 105 cases of visceral leishmaniasis were diagnosed from findings of Leishman-Donovan bodies. Prominent nuclear dyserythropoiesis was shown in 17 patients, 14 of whom had the frank type that is uniquely seen in congenital dyserythropoietic anemia type II. Most of these cases showed an extremely low degree of marrow parasitemia. This degree of nuclear dyserythropoiesis was not found in the majority of the marrows in which parasites were more easily detected. There is a direct and negative correlationbetween frank nuclear dyserythropoiesis and marrow parasitemia. Extended microscopical examination is recommended for the detection of Leishman-Donovan bodies in cases of suspected visceral leishmaniasis when frank dyserythropoiesis is a prominent feature. It is possible that both frank nuclear dyserythropoiesis and marrow parasitemia are etiologically under the influence of a common chemokine or cytokine.

Piebaldism associated with congenital dyserythropoietic anemia type II (HEMPAS).

Congenital dyserythropoietic anemias (CDAs) are a group of relatively rare inherited anemias. They are characterized by ineffective erythropoiesis and classified as three major groups and a number of variants. CDA type II, also known as hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), is the most frequent one. A number of associations with CDA II have been reported, although each described only one or a few patients. Here we presented a piebald woman with vaginal atresia who was tested for anemia and diagnosed as CDA type II. Piebaldism and anemia association were previously described in the mouse. Our case was the first that shows the features of both piebaldism and CDA in the same patient. This association may suggest a stem cell defect to cause both hematopoietic and cutaneous manifestations.

Identification of a novel simian parvovirus in cynomolgus monkeys with severe anemia. A paradigm of human B19 parvovirus infection.

Although human B19 parvovirus infection has been clearly associated with a number of distinct syndromes (including severe anemia, abortion, and arthritis), detailed knowledge of its pathogenesis has been hindered by the lack of a suitable animal model. We have identified a novel simian parvovirus in cynomolgus monkeys with severe anemia. Sequencing of a 723-bp fragment of cloned viral DNA extracted from serum revealed that the simian parvovirus has 65% homology at the DNA level with the human B19 parvovirus but little homology with other known parvoviruses. Light microscopic examination of bone marrow from infected animals showed intranuclear inclusion bodies, and ultrastructural studies showed viral arrays characteristic of parvoviruses. Another striking feature was the presence of marked dyserythropoiesis in cells of the erythroid lineage, raising the possibility that B19 parvovirus infection may underlie related dyserythropoietic syndromes in human beings. Affected animals had concurrent infection with the immunosuppressive type D simian retrovirus, analogous to HIV patients who develop severe anemia because of infection with B19 parvovirus. The remarkable similarities between the simian and B19 parvoviruses suggest that experimentally infected cynomolgus monkeys may serve as a useful animal model of human B19 infection.