[CIS PIDD] [cis-pidd] VS: assistance with patient case with ALPS-like disease

Wed Apr 11 03:56:22 EDT 2018

Hi Kate,

Combination of encephalopathy and ALPS-like is HIGHLY suggestive of FADD, actually unique to it, is there even some reversible hepatopathy?  Any signs of functional hyposplenism in the peripheral blood smear? --> is this still FADD, could even be with somewhat different phenotype than the reported one?
If it looks like a duck, walks like...

I suggest that you still have the WES and gene panel sequencers visually check FADD and report its coverage? Were all exons and introns covered? Any small deletions gone unnoticed? Any flanking region mutations?

Even if nothing were found, I still suggest that FADD with introns and flanking regions may need to be re-sequenced, especially if there were gaps in coverage, this could be done as either singly or as part of WGS (the latter may cost the same as the first option...)?

Contact J-L Casanova and Anne Puel? Even if there in the end is nothing in FADD, I would look at the FADD connectome and then search for something novel in that? And if there is only a heterozygous VUS in FADD that could turn out to be a dominant negative mutation (not described yet)?

Hope this helps!

ATB

Mikko

Mikko Seppänen, MD, PhD, Adjunct professor
Head
Helsinki University Central Hospital, Rare Disease Center
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Lähettäjä: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] Puolesta CIS-PIDD
Lähetetty: 11. huhtikuuta 2018 0:44
Vastaanottaja: CIS-PIDD <cis-pidd at lyris.dundee.net>
Aihe: [cis-pidd] assistance with patient case with ALPS-like disease

Greetings:

I am looking for any advice on next step management of this difficult case.  Basically its a 13 year old male with lymphoproliferation.  ALPS-like disease  (lymphoproliferation of CNS and lungs (chronic lymphocytic interstitial pneumonitis) and generalized lymphadenopathy) he has had major flares of CNS that caused encephalopathic event and since then most recently, again a flare that presented clinically as seizures.  WES has been normal. Currently managed on sirolimus.  Heme/Onc has plan for MUD---(a less than perfect match).  I have hesitation for transplantation, because there is no definitive diagnosis and hence lack of ability to define risk of transplant.Alternatively Heme/Onc feels that this lymphoproliferation will continue and if unchecked will devastate him, and hence they are leaning toward transplant.

>From an immune system perspective.  I have been left with some minor abnormalities on testing, that to this point are being addressed with monthly IVIG (he has not been getting infections) C2 1.4 (low), C3 190, C4 12; Total Complement 61. IgE 16 and Immunocap negative. Strep Pneumo 23 serotypes tested and low; Repeated 3 months after Pneumovax-23 and normalized. Tetanus Ab normal. Lymphocyte Antigen Proliferation and Mitogen Screen performed with low lymphocyte responses to candida, tentanus, PHA, and Con A. Extended B Cell Phenotyping performed which showed relative increase in naïve B cells with relative decrease in switched memory B cells and relative increase in Transitional B cells.

Thank you in advance for any thoughts, or suggestions.

Much Appreciated! Below is a brief history, and below that is a more detailed history.

Brief Clinical History:

Patient is a 13 year old male. was initially diagnosed with autoimmune hemolytic anemia in 2016 and recovered. He developed mumps and generalized lymphadenopathy in April/May 2017 including lung biopsy consistent with chronic Lymphocytic Interstitial Pneumonitis, pathognomonic for ALPS. However, Cincinnati genetic panel (CASP8, CASP10, FADD, FAS, FASLG, ITK, KRAS, MAGT1, NRAS) were negative for ALPS mutations so he was referred to as ALPS-like. He was treated with HD steroids and Sirolimus in June 2017 after lymph node biopsy. He did well with some intermittent erythema nodosum and shortness of breath until September 2017 when he became encephalopathic and was admitted to the PICU with diffuse ischemic white matter changes suggesting an acute demyelinating process. This rapidly improved on HD steroids, IVIG x1, and he was discharged on Sirolimus. Genetics unable to perform Whole Exome Sequencing at that time; I sent for CVID panel via Invitae (CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12 DCLRE1C GATA2 JAK3 RAG1 STXBP2) - negative. He has been EBV and CMV negative in the past. He has since had hypogammaglobulinemia on monthly IVIG (unsure if this was steroid induced or not). He was started on monthly 5-day steroid pulses in September 2017. Continues on Sirolimus. Developed seizures in February 2018 controlled on Keppra and found to have active waxing/waning demyelinating process on MRI and was given high dose steroids with rapid improvement. WES returned early March 2018 and completely negative. Currently, he is at his baseline.

-----------------------------------------

Detailed Clinical History:

Patient initially presented in April 2016 as an 11yo with Hx of ADHD and obesity with 1 month of fatigue, 2 weeks of headaches, 1 week of URI symptoms, 5 days of orange colored urine, 2 days of jaundice. No significant lymphadenopathy on exam. He had been recently diagnosed with sinus infection by PMD exam and completed Azithromycin. Lab work on admission demonstrated: CBC - 3.8 > 4.9 < 230 (MCV 83, %N 57.7, %L 33.0) with a smear showing mild increase in elliptocytes, occasional reactive lymphocytes, elevated reticulocyte count to 2.7%, elevated LDH to 337, low haptoglobin to 22, but DAT negative. CMP normal. EBV, CMV, Parvovirus Mycoplasma negative and IgGAM normal (IgG 1070, IgA 26, IgM 77) with normal Hgb ID, coags, G6PD. He was hospitalized, transfused 2 unit pRBCs and discharged with a Hgb 8.1. This improved to 9.8 over 1 month but labs still demonstrated a smoldering hemolysis with haptoglobin <8, LDH 309, retic 6.5% and smear still positive for occasional elliptocytes; polychromasia, cells resembling bite cells. He also had worsening headaches.

In July 2016, he was re-hospitalized for a Hgb of 7.1, Tbili 2.9, DAT IgG first time positive with allo Anti-E antibody and antibody with Anti-N-like specificity identified. Diagnosed with AIHA, treated for the first time with steroids: Methylprednisolone 50mg IV q8 x 3 days and sent home on Prednisone taper. An immunodeficiency profile sent during acute phase: Increase in double negative (CD4-CD8-) T lymphocytes with an increase in double negative TCR alpha/beta+ cells constituting approximately 4.8% of the total CD3+ cells. When he was stable, Mayo Hemolytic Anemia panel was sent and negative. His Hgb recovered by August to 14.7, retic 1.2%, Tbili 0.5.

He did well until February 2017 when he developed persistent fevers, cough, SOB, and then developed lymphadenopathy. PMD diagnosed patient with mumps but IgM negative. He did do a CXR which showed perihilar infiltrates and bilateral atelectasis with small nodular opacities. This was followed up with CT Chest which showed extensive lymphadenopathy of mediastinum, hila, infraclavicular, and diaphragmatic regions as well as the upper abdomen. Marked splenomegaly. Extensive solid and ground-glass nodular and patchy opacities throughout the bilateral lungs. During this time, his Hgb also started dropping from 12.2 to 10.9 with a slight rise in ESR (2 to 8), CRP (0.99 to 1.36), and normal IgGAM. He did have a BAL which demonstrated no infectious etiology but iron stain positive in 3% of alveolar macrophages; fluid reviewed and demonstrated predominance of alveolar macrophages and lymphocytes. Detailed infectious workup negative: HIV negative, Histoplasma negative, Fungal and Blood cultures negative, quantiferon negative, galactomannan/beta-d-glucan negative. He had a CT abdomen/pelvis at the end of the month which showed extensive lymphadenopathy in the upper abdomen, retroperitoneum, and pelvis. Marked splenomegaly (22.5 cm craniocaudally) and more modest hepatomegaly. Incidental left adrenal nodule measuring 9 mm. Unchanged lung bases. Immunodeficiency profile was sent to Cinci for ALPS and demonstrated 7.3% TCR a/b DNTC, no increased B220+ TCR a/b DNTC, decreased HLA DR, and decreased CD27+ B cells, fitting 3 of 4 criteria for ALPS based on their algorithm.

In June 2017, A&I saw the patient. C2 1.4 (low), C3 190, C4 12; Total Complement 61. IgE 16 and Immunocap negative. Strep Pneumo 23 serotypes tested and low; Repeated 3 months after Pneumovax-23 and normalized. Tetanus Ab normal. Lymphocyte Antigen Proliferation and Mitogen Screen performed with low lymphocyte responses to candida, tentanus, PHA, and Con A. Extended B Cell Phenotyping performed which showed relative increase in naïve B cells with relative decrease in switched memory B cells and relative increase in Transitional B cells. Cincinnati ALPS 9-gene panel returned negative (CASP8, CASP10, FADD, FAS, FASLG, ITK, KRAS, MAGT1, NRAS). ANA negative. The patient had a cervical lymph node and right lung biopsy performed which demonstrated follicular hyperplasia in the LN and chronic lymphocytic interstitial pneumonitis in the lung. Based on a presumptive diagnosis of ALPS, the patient was admitted for a scheduled admission for 3 days of Methylprednisolone 1 gm BID and Sirolimus 2mg daily. He did well after this.

In September 2017, he developed erythematous nodules on shins bilaterally concerning for EN, intermittent SOB and coughing. Dermatology biopsied the nodules and found a very mild superficial and moderate deep lymphohistiocytic infiltrate with eosinophils and fat necrosis. He was sent home but then 10 days later presented to the ED and was admitted to the ICU for the worst headache of his life, confusion, lethargy, and vomiting. Normal CBC, CMP, infectious workup negative - CSF predominantly lymphocytes without flow evidence of monomorphic population / blasts. However, MRI/MRA brain showed patchy increased T2 and FLAIR signal in the bilateral corona radiata, basal ganglia, posterior limb of  right internal capsule, and temporal lobes, predominantly involving the white matter; focal enhancement in right anterior temporal lobe suggestive of acute demyelinating lesion. CT Chest showed continued patchy ground-glass opacities in the bilateral lungs; changes in right lobes most concerning for multifocal pneumonia; Significant interval improvement in the previously seen bilateral pulmonary nodules. His encephalopathy and overall condition rapidly improved on Methylprednisolone 1gm q8 x 5 days, continued on Sirolimus. For the first time, his IgGAM dropped - IgG 340, IgA 9, IgM 13 and so he was given IVIG given 600mg/kg. Invitae CVID panel was sent and negative (CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12 DCLRE1C GATA2 JAK3 RAG1 STXBP2). He completed a course of lovenox and augmentin as well.

His disease was well controlled on monthly 5 day Dexamethasone pulses and monthly IVIG, continued on Sirolimus with a goal level of 15. However, he developed seizures in February 2018 and repeat MRI brain showed Numerous patchy/ill-defined foci of abnormal T2/FLAIR signal intensity throughout the brain, predominantly involving the cerebral white matter, most compatible with a waxing/waning pattern of nonspecific demyelination. His seizures were controlled on Keppra. Repeat CT C/A/P showed improvement in all of his lymphadenopathy and decrease in his HSM. Normal detailed ophtho exam. Sent home after finishing 3 days of methylpred back at his baseline.

In March 2018, WES was completed and completely negative. Pending MUD transplantation with less than perfect matched donor (9/10 with mismatch at A allele).

Kate Ruda Wessell, DO
Division of Pediatric Allergy/Immunology
Rainbow Babies and Children's Hospital
Clinical Assistant Professor,  Pediatrics
Case Western Reserve School of Medicine

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