Neonatal Autoimmune Lymphoproliferative Syndrome: A Case Report and A Brief Review.

The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life.

Underlying CTLA4 Deficiency in a Patient With Juvenile Idiopathic Arthritis and Autoimmune Lymphoproliferative Syndrome Features Successfully Treated With Abatacept-A Case Report.

BACKGROUND: Functional variants of the cytotoxic T-lymphocyte antigen-4 (CTLA4) could contribute to the pathogenesis of disorders characterized by abnormal T-cell responses. CASE PRESENTATION: We report a case of a 13-year-old girl who first presented with polyarticular juvenile idiopathic arthritis poorly responsive to treatment. During the following years the patient developed cytopenias, chronic lymphoproliferation, high values of T-cell receptor αß+ CD4- CD8- double-negative T cells and defective Fas-mediated T cells apoptosis. Autoimmune lymphoproliferative syndrome was diagnosed and therapy with mycophenolate mofetil was started, with good hematological control. Due to the persistence of active polyarthritis, mycophenolate mofetil was replaced with sirolimus. In the following months the patient developed hypogammaglobulinemia and started having severe diarrhea. Histologically, duodenitis and chronic gastritis were present. Using the next generation sequencing-based gene panel screening, a CTLA4 mutation was detected (p.Cys58Serfs*13). At the age of 21 the patient developed acute autoimmune hemolytic anemia; steroid treatment in combination with abatacept were started with clinical remission of all symptoms, even arthritis. CONCLUSIONS: Targeted immunologic screening and appropriate genetic tests could help in the diagnosis of a specific genetically mediated immune dysregulation syndrome, allowing to select those patients who can take advantage of target therapy, as in the case of abatacept in CTLA4 deficiency.

Use of Sirolimus (Rapamycin) for Treatment of Cytopenias and Lymphoproliferation Linked to Autoimmune Lymphoproliferative Syndrome (ALPS). Two Case Reports.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis. Children present with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias. Recent advances show efficacy of treatment with immunosuppressive drugs. Sirolimus, an mammalian target of rapamycin inhibitor, improves autoimmune cytopenias and lymphoproliferation, with a safe profile. We present 2 patients, a 5-year-old girl and 15-year-old boy, diagnosed with ALPS with initial partial response to steroid treatment. Autoimmune cytopenias and lymphoproliferation then became refractory to treatment, with recurrence of symptoms. In both cases, treatment with sirolimus was started, with a rapid response, complete remission of cytopenias, and resolution of lymphoproliferation, with no significant adverse effects. CONCLUSION: sirolimus is an effective and safe drug for controlling children with cytopenias and lymphoproliferation linked to ALPS.

[Effect of danazol treatment on growth in pediatric patients with hereditary angioedema due to C1-inhibitor deficiency]. / A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére.

INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.

Recommendations on the clinical use of bendamustine in lymphoproliferative syndromes and multiple myeloma.

Bendamustine is an increasingly used hybrid alkylating agent that is active in lymphoid neoplasias via a novel mechanism of action. There are some pending questions about its use in clinical practice because of its developmental features. A consensus panel of several leading Spanish hematologists with broad experience in the clinical use of bendamustine has established recommendations for the management and treatment of hematological patients with bendamustine based on available clinical data and the experience of the participants. These recommendations address the dose and treatment regimen for different clinical indications, the management of toxicity, and support therapy. This article contains the conclusions of this consensus panel, which are intended to serve as guidelines for the use of bendamustine.

Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS).

PURPOSE: Autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant genetic disorder of lymphocyte homeostasis with defective Fas-mediated apoptosis. Current therapies for ALPS primarily target autoimmune manifestations with non-specific immune suppressants with variable success thus highlighting the need for better therapeutics for this disorder. METHODS: The spectrum of clinical manifestations of ALPS is mirrored by MRL/lpr mice that carry a loss of function mutation in the Fas gene and have proven to be a valuable model in predicting the efficacy of several therapeutics that are front-line modalities for the treatment of ALPS. We evaluated the potential efficacy of tofacitinib, an orally active, pan-JAK inhibitor currently approved for rheumatoid arthritis as a single agent modality against ALPS using MRL/lpr mice. RESULTS: We demonstrate that a 42-day course of tofacitinib therapy leads to a lasting reversal of lymphadenopathy and autoimmune manifestations in the treated MRL/lpr mice, Specifically, in treated mice the peripheral blood white blood cell counts were reversed to near normal levels with almost a 50 % reduction in the TCRαß(+)CD4(-)CD8(-)T lymphocyte numbers that coincided with a parallel increase in CD8(+) T cells without a demonstrable effect on CD4(+) lymphocytes including FoxP3(+) regulatory T cells. The elevated plasma IgG and IgA levels were also drastically lowered along with a significant reduction in plasmablasts and plasmacytes in the spleen. CONCLUSION: On the basis of these results, it is likely that tofacitinib would prove to be a potent single agent therapeutic modality capable of ameliorating both offending lymphadenopathy as well as autoimmunity in ALPS patients.

Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase Cδ Deficiency.

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.

Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells, and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG). METHODS: ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays. RESULTS: This report describes the cases of a patient who presented a severe form of ALPS-FASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity, and AICD in T-cell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing Epstein-Barr virus (EBV)-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients. CONCLUSION: Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy.

Autoimmune lymphoproliferative syndrome in pregnancy: a case of favorable mother-fetal outcome in a well-controlled disease.

The autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by the dysregulation of the Fas apoptotic pathway. The Fas gene is expressed at the maternal-fetal interface and is involved in the regulation of immune response and implantation. Altered Fas expression may result in altered apoptosis and, ultimately, affect both the immune response and implantation; it is in fact associated with recurrent pregnancy loss, preterm premature rupture of membranes and pre-eclampsia. Currently, there are over 500 cases of ALPS reported worldwide from various racial and ethnic backgrounds. Up to date, the published work contains no specific reports on pregnancy outcome in women affected by ALPS. We present a case of full-term uneventful pregnancy in a patient affected by ALPS. A specific clinical follow-up in a pregnant woman with primary immunologic disease is suggested.

Autoimmune lymphoproliferative syndrome: an update and review of the literature.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.

Erythematous rash following romiplostim administration in a patient with autoimmune lymphoproliferative syndrome.

OBJECTIVE: To report a case of erythematous rash induced by romiplostim administration in a patient with autoimmune lymphoproliferative syndrome (ALPS). CASE SUMMARY: A 19-year-old female with ALPS-related thrombocytopenia (platelet count 4 × 10(3)/µL) successfully treated with romiplostim 500 µg weekly for 9 months presented with a grade 3 maculopapular rash. Symptoms on presentation included purpuric, erythematous pustules confined to the trunk following romiplostim administration the previous day. A punch biopsy of skin from the patient's right lower abdomen revealed perivascular chronic inflammation with numerous eosinophils consistent with drug reaction. The patient had received romiplostim 500 µg weekly with no other reports of rash until this time. Romiplostim was discontinued, the patient was monitored, and the rash resolved within 1 week. Romiplostim was then restarted at 200 µg weekly. The patient has achieved platelet normalization at a current romiplostim dose of 250 µg weekly with no further adverse reactions. DISCUSSION: ALPS is a rare autoimmune disorder with approximately 500 known cases worldwide. Pharmacotherapy for ALPS patients generally targets autoimmune cytopenias associated with the disorder. When standard therapies for ALPS-related cytopenias fail, clinicians are often forced to consider novel treatment options. Our patient had ALPS-related thrombocytopenia that was treated with romiplostim, which resulted in grade 3 maculopapular rash after almost 1 year of treatment. The likelihood that this patient's erythematous rash was due to romiplostim administration was determined to be possible based on the Naranjo probability scale. The reaction was reported to the drug manufacturer and to the Food and Drug Administration's MedWatch program. CONCLUSIONS: This is the first documented case, to our knowledge, of severe maculopapular rash occurring less than 24 hours after romiplostim administration for treatment of ALPS-related chronic thrombocytopenia. Rash has been reported as an adverse event of romiplostim therapy at higher doses (750 µg), but not at a dose of 500 µg. This report also describes successful rechallenge of romiplostim after resolution of the rash.

New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome.

PURPOSE OF REVIEW: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review. RECENT FINDINGS: A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency, have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS-specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease. SUMMARY: On the basis of novel advances, the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients.

Pentostatin for treatment of refractory autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS), a disorder of programmed cell death, could be due to a congenital defect in the Fas signaling pathway or other pathways for apoptosis. Most cases present with lymphoproliferation and certain autoimmune features such as thrombocytopenia, neutropenia, and anemia are due to excessive production of antibodies by B lymphocytes. Majority of cases present within the first few years of life. We report a case of ALPS presenting at birth which was refractory to splenectomy and immunosuppressive therapy, but responded to pentostatin followed by hematopoietic stem cell transplantation (HSCT).

Mycophenolate mofetil-induced pseudotumor cerebri in a boy with autoimmune lymphoproliferative disease.

INTRODUCTION: Pseudotumor cerebri (PTC) is a syndrome characterized with increased intracranial pressure, normal cerebrospinal fluid content (CSF), and a normal brain on imaging studies. In this case report, PTC has been linked to mycophenolate mofetil (MMF) that has been used for autoimmune lymphoproliferative syndrome (ALPS). CASE REPORT: A 5-year-old boy, who was using MMF for 4 months because of the ALPS, suffered from occipital headache and vomiting with no other symptom. The initial physical examination was normal expect bilateral papilledema. The patient underwent a lumbar puncture which showed elevated opening pressure (590 mmH2O) but no laboratory abnormalities of the CSF. A diagnosis of PTC was established. MMF was stopped, and the child was started on an acetazolamide treatment for 2 weeks. His symptoms and complaints recovered after this treatment. DISCUSSION: According to our knowledge, we report the first case of MMF-induced PTC in a boy with ALPS. This case illustrates that despite the rarity of MMF-induced PTC, the physicians should be aware of this possibility. Furthermore, in the setting of new-onset headaches or visual changes, early ophthalmologic examination for papilledema is recommended for early diagnosis.