Neurofibromatosis is a genetic autosomal dominant disorder consisting in cutaneous, neurologic, ophthalmologic and tumoral signs. But other disorders that can mimic neurofibromatosis should be excluded.
A 10-year-old girl, from consanguineous gipsy parents, was admitted for anemia. Family history showed a sister who died due to cerebral tumors at the age of 3. The personal medical history was insignificant.
The clinical examination revealed more than 6 „cafe au lait” spots larger than 0,5cm and multiple axillary freckling, signs which support the diagnosis of neurofibromatosis. The clinical exam of the parents was normal. Laboratory explorations showed a normochromic, normocytic anemia, with normal ferritin level, a folic acid deficiency, normal liver and kidney function, but also immunological abnormalities: IgA, IgG2 and IgG4 deficiency, poor response to vaccination, low memory B cells and a normal number of T, CD4+, CD8+ and NK cells. Ophthalmologic examination was normal. Multiple tumors with the diameter between 0,5 and 4 cm were noted during the cerebral MRI-scan. In evolution, she displayed recurrent episodes of seizures. The cerebral biopsy revealed a diffuse astrocytoma IDH mutant and she started chemotherapy. Taking in account the consanguinity, family history and the negative clinical exam of the parents we performed genetic exam – WES that revealed a pathogenic homozygous c.2653A>T mutation in MSH6 gene, parents being carriers for the same mutation.
In atypical cases of neurofibromatosis associating immunological abnormalities, DNA repair syndromes must be excluded. A correct diagnosis allows genetic counseling and monitoring for the cancer development in other members of the family.
Ataxia-telangiectasia (AT) is an autosomal recessive disease that associates combined immunodeficiency with progressive cerebellar ataxia. It is characterized by cerebellar ataxia, oculocutaneous telangiectasia, increased susceptibility to infections, hypersensitivity to radiation and predisposition to malignancy. The aim of this observation is to describe leukemia therapeutic features in AT.
We present a patient with AT complicated by acute leukemia followed in the pediatric immune-hematology unit. The diagnosis and management of Leukemia were retrospectively analyzed.
B.I. was followed of AT since 5-year-old. She has been regularly substituted by intravenous immunonoglobulin in addition to anti-infectious prophylaxis. At 14-year-old, she developed acute non-hyperleucocytic T-lymphoblastic leukemia without meningeal involvement. She was treated according to the EORTC58081 protocol (modified). She was allocated to the Avereage Low Risk group (AR1) instead of Average High Risk (AR2). A good response to the prophase was obtained. Induction chemotherapy drugs was decreased (Vincristine from 1.5mg/m2 to 0.7mg/m2 and Daunorubicine from 30 to 10mg/m2). Despite this, the protocol was suspended for 15 days from the 12th day of induction due to severe liver cytolysis and cholestasis. The patient didn’t present medullary aplasia. Chemotherapy was interrupted again at the 28th day of induction because of fever and refractory hypoxemia. She was treated with broad-spectrum antibiotic. She died at 47 days of the beginning of chemotherapy. The post mortem bone marrow aspiration showed a complete remission of leukemia.
Patients with AT present chromosomal instability due to a DNA repair disorder. This may explain severe chemotherapy side effects even at low doses.
Hypomorphic homozygous mutations of LIG4, encoding DNA ligase IV, cause a wide spectrum of developmental and immune defects, from SCID presentations to a phenotype resembling other chromosomal instability syndromes. Most patients present growth failure, microcephaly, facial dysmorphism, mental retardation, diverse skin and bone manifestations, and immunodeficiency ranging from SCID to humoral deficiency. Isolated bone marrow failure and hematological malignancies have also been reported.
Whole exome sequencing (WES) was performed in a 24-year-old man who was healthy until the age of 16 years-old, when he manifested hidradenitis suppurativa. At 18, he was hospitalized for pneumonia, which resolved uneventfully. At the age of 21 he had a complicated Haemophilus influenzae pneumonia. At that time he was found to have absent IgG, IgA and IgM, no responses to recall antigens, no B cells yet normal T-cell subset. He is a tall, overweight patient with no dysmorphic features and no bone abnormalities, but presenting vitiligo. The patient has been on SCIg replacement and is asymptomatic since diagnosis.
WES identified a homozygous mutation in LIG4 (p.R278H), previously reported as pathogenic, resulting in radiosensitivity and in a subtle VDJ recombination defect. Two other homozygous patients have been described, with very different phenotypes: one with normal development and radiosensitivity manifested as detrimental response to acute leukemia therapy, and one with developmental delay, dysmorphic features and pancytopenia.
We report the first DNA Ligase IV deficient patient with isolated late-onset agammaglobulinemia as unveiled by an unbiased sequencing approach.
Autosomal recessive mutations in BLM underlie Bloom syndrome, a prototypical chromosomal instability syndrome resulting in growth retardation, cancer and immunodeficiency. Other features include a typical face, various skin lesions, diabetes mellitus, and infertility. To date, more than 60 pathogenic variants in BLM have been identified. Despite the lack of definitive treatment, early diagnosis is crucial for optimal follow-up of patients, especially regarding their increased cancer susceptibility.
Whole exome sequencing (WES) was performed in a 14-year-old girl with high-pitched voice, long and narrow face, microcephaly, recurrent respiratory tract infections, hypogammaglobulinemia, short stature and early-onset type 2 diabetes mellitus. She didn’t have skin manifestations, including the prototypic sun-induced face rash.
WES identified a novel private homozygous variant in BLM (p.L753X), causing a stop gain in the DNA helicase domain and predicted to be pathogenic by in silico prediction methods (CADD score 38, MSC 0.08). Functional validation of the variant is ongoing.
We report a novel mutation in BLM in a teenager with some phenotypic manifestations of Bloom syndrome, but lacking the usual skin manifestations.
Patients with ataxia telangiectasia (AT) often show high copy numbers of Epstein-Barr virus (EBV) in their peripheral blood. This observation was supported by AT-animal model data that showed the role of AT-causing gene, ATM, for an optimal adaptive immune response against EBV. A sub-group of AT patients with elevated IgM levels have more severe phenotype and decreased survival compared to those with normal IgM. To the best of our knowledge, severe EBV infection has not been described in this sub-group of AT.
We describe a girl diagnosed with hyper IgM AT at the age of 3 years. At the time of diagnosis serum immunoglobulins were IgM 12.8, IgA <0.1, IgG <0.5 g/L, IgE < 2 kU/L. Blood EBV DNA level measured by PCR was negative as well as EBV immunoglobulin M antibody.
Six months after the diagnosis, the patient developed fever, pancytopenia and hepatosplenomegaly. Blood PCR EBV level was 60100 copies/mL. Acyclovir did not control the symptoms and EBV DNA load. A treatment with rituximab was started with significant improvement of her symptoms. EBV PCR became negative 14 days after initiation of rituximab, and resolution of hepatosplenomegaly was observed during follow-up as well. Unfortunately, the later course of AT was complicated by cryptosporidiosis and severe bacterial infections despite regular immunoglobulin and antimicrobial treatment and the patient died at the age of 6 years.
This report broadens the previous knowledge that the sub-group of AT with hyper IgM is at risk of developing severe infections, including EBV.
With advance of genetic methods PID patients with complex phenotype caused by multiple genetic defects are more frequently described. They present a challenge in immediate symptoms treatment as well as in deciding on curative therapy approach.
We describe a 12 month old female patient with ATM gene compound-heterozygous mutations (с.5932G>T; c.1561_1562delGA) and 4p16.3 microduplication.
Patient’s symptoms included dysmorphic facial features, combined immunodeficiency, elevated alpha fetal protein and cytopenia since the age of 6 months (transfusion-dependent anemia and thrombocytopenia, and neutropenia). Based on bone marrow histology she was diagnosed with myelodysplastic syndrome, yet her thrombocytopenia was refractory to transfusions due to autoimmune component. Treatment with IVIG, high-dose methylprednisolone, romiplostim and rituximab was ineffective. The patient received haploidentical hematopoietic stem cell transplantation (HSCT) complicated by primary graft dysfunction. In preparation for the second HSCT the patient was treated with daratumumab 16 mg/kg every 2 weeks # 4 with partial response of her cytopenia. Second haploidentical HSCT with Fludarabine (150 mg/m2 days − 6 to − 2), Thiotepa (10 mg/kg days -5 to -4), Thymoglobulin (5 mg/kg days -5 to -4), Rituximab (100 mg/m2 day -1), Plerixafor (720 mkg/kg days -6 to -4) conditioning and TCR alfa/beta/CD19 depletion was performed. Granulocytes engraftment was recorded on day +17. Right now the patient in the early post-HSCT period, doing well.
We present challenges in combined cytopenia treatment in a patient with complex PID phenotype and demonstrate partial response to daratumumab.
DNA repair defects are rare, hereditary diseases with heterogenous manifestations but sharing clinical features as immune deficiency, cancer predisposition, growth retardation, neurological disorders.
We present four patients; two pairs of siblings, with Bloom and Nijmegen Breakage Syndrome.
P1F1:18-year-old boy product to consangenious parents, had growth retardation and recurring otitis. Telangiectasies, typical facies and high sister chromatid exchanges suggested Bloom. He had hypogammaglobulinemia, absent polysaccharide antibody responses. Surgically removed upper right abdominal mass at age 4 was found to be Wilms tumor. He received chemotherapy for stage I, achieved complete remission without drug toxicity or relapse.
P2F1:12-year-old girl had growth retardation, recurring upper respiratory tract infections, cafe-au-lait spots on trunk, a giant nevus on her leg. She had hypogammaglobulinemia and received IVIG, antibacterial, antifungal prophylaxis, infections/year decreased on follow-up. She has not developed malignancy.
P1F2:9-year-old girl product to nonconsanguineous parents, was born with microcephaly, anal atresia, rectovaginal fistula and left ectopic pelvicaliectatic kidney. By age 9, along with dysmorphic findings, she had hepatosplenomegaly and mediastinal lymph nodes. She received rapamycine treatment for lymphoproliferation with partial response. Liver biopsy showed lymphoid infiltration but not lymphoma. She was started on IVIG and antibacterial prophylaxis.
P2F2:Patient was born at 28 weeks of gestation, weighing 1400 gr with microcephaly. At age 5, he had mild hypogammaglobulinemia and B-cell lymphopenia. Whole exome sequencing was performed for both siblings, revealing a homozygous mutation in NBS1 gene (del657_661).
Patients should be carefully evaluated for expected malignancies in case of primary immune deficiencies, especially under the category of DNA repair defects.
Patients with severe combined immunodeficiency (SCID) usually presents with severe infections. This case is presented to highlight the severe autoimmune manifestation, sever microcephaly and disseminated CMV infection in a child with SCID.
A 2-month-old boy, born to a consanguineous marriage, presented with a generalized erythematous rash and recurrent diarrhoea. At 7 months of age, he developed respiratory distress. At 9 months of age, he started developing recurrent episodes of anaemia requiring packed red cell transfusions. Physical examination revealed failure to thrive and significant microcephaly, bilateral undescended testes, spleno-hepatomegaly and bilateral chest crepitations.
He had anemia and thrombocytopenia. Absolute lymphocyte count was 2.14 x109/L. Peripheral blood smear revealed signs of haemolysis and positive Direct Coombs Test. Blood CMV PCR was positive and viral load was 56722 copies/ml. IgG- 3.33 g/L (3.7-15.80), IgA - <0.17 g/L (0.30-1.30), IgM- 1.19 g/L (0.60-1.20) and IgE <2 IU/ml (up to 32). Lymphocyte subsets showed markedly reduced B cells. Flowcytometry showed CD4/CD8 reversal, decreased naïve T cells, increased HLA DR expression on CD3+ T cells. For autoimmune hemolytic anemia, intravenous immunoglobulin (IVIg) 1 gm/kg was given and also required high dose steroids. He required additional therapy IVIg and oral sirolimus (at 1 mg/m2), following which there was gradual recovery. Possibility of SCID was considered. Whole exome sequencing revealed frameshift mutation in NHEJ1 c.544_545delGA, p.Glu182fs.
Severe microcephaly and growth retardation in context of SCID can be clue toward diagnosis. In patients with refractory severe autoimmune haemolytic anemia, one may consider addition of sirolimus.
RAG2 is an essential gene, encoding enzymes involved in recombination of genes for Immunoglobulin and T-cell receptor proteins. Several mutations have been described, with a variety of clinical phenotypes ranging from severe combined immunodeficiency (SCID) to autoimmunity.
For most-severe manifestations, Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) is the standard treatment. This carries significant risk of mortality. Better outcomes are expected if performed in infancy. Delay resulting in advanced disease may preclude this being an option.
Gene therapy is rapidly advancing with opportunity to develop new ways of approaching treatment options.
We review a patient case and consider feasibility of genetic screening in patients with CVID and evaluate outcomes of Bone marrow transplantstion in similar cases.
Patient case review: 40-year-old female, presenting aged 25 with Myasthenia gravis and incidental discovery of B and T cell lymphopenia, alongside recurrent infections. Aged 29 she developed autoimmune macrophagic myofascitis. Aged 39 she was enrolled onto the BRIDGE study with identification of a likely pathogenic novel RAG2 gene mutation. We review the timeline of events. We discuss evaluation for Bone marrow transplant and available literature for outcomes in similar cases.
Early genetic screening may be helpful in selecting appropriate patients with immunodeficiency for bone marrow transplantation, but more data is needed.
This case highlights the challenges associated with decision making when approaching treatment options in patients, where literature for genetically and phenotypically similar, but not identical patients, is available.
NBS is rare autosomal recessive DNA-repair disorder, characterized by microcephaly, facial dysmorphy, skin pigmentation defects, combined immunodeficiency, chromosomal instability, and high predisposition to malignancy. Most patients are of Slavic origin and carry same homozygous deletion (c.657_661del5) of NBN gene. There are only few case reports on cutaneous manifestations of NBS in literature, so we sought to delineate dermatological features of big series of Polish NBS patients.
The study was performed as a part of ERA-NET-E-Rare-3/l/EuroCID/04/2016 grant in CMHI, Warsaw. All patents had detailed cutaneous examination, other data were extracted from patients' charts.
52 patients (22M, 30F) from 49 families were interviewed and examined. Median age at assessment was 11,8 years (range 6 months-39 years). Three patients underwent stem cell transplantation 2-11 years before examination. Pigmentation anomalies included café-au-lait spots (91%), hypopigmented macules (52%), melanocytic nevi (48%). 39% of patients presented with persistent form of vasculitides (livedo reticularis) and Raynaud’s phenomenon, which needs further elucidation. Granulomatous skin lesions were clinically diagnosed in 23% of cases, in 15,5% being histologically confirmed. In 2 cases of atopic/eczematous-like erythrodermia, skin biopsy also revealed granulomatous changes. Autoimmune complications (vitiligo, alopecia) showed 4 and 2 patients, respectively. Other frequent manifestations included progeric skin changes, premature hair graying and thin/sparse hair. Surprisingly, any infectious skin complication were observed.
Rarity of disease suggests this is largest clinical study of cutaneous manifestation involving 52 living NBS patients. Most frequent skin lesion, besides skin pigmentation defects, are form of vasculitides/Raynaud’s phenomenon. Incurable, progressive skin granulomas are most challenging in diagnosis and treatment.