[CIS PIDD] [cis-pidd] VS: Peruvian 10-yr-old girl with novel PIDD?

[Juan Carlos Aldave Becerra]

Dear professors,
Thank you for your kind suggestions. I will keep you updated.
Sincerely,
Juan


> From: Mikko.Seppanen at hus.fi

> To: srosenzweig at cc.nih.gov; jucapul_84 at hotmail.com

> Subject: VS: Peruvian 10-yr-old girl with novel PIDD?

> Date: Tue, 13 May 2014 13:51:01 +0000

> 

> BTW Juan, 

> 

> In my experience - if it is a known gene - Kate is almost always correct. Sergio's suggestion about DNA repair defects in general is valid as well, of course. 

> 

> Mikko

> 

> -----Alkuperäinen viesti-----

> Lähettäjä: Rosenzweig, Sergio (NIH/CC/DLM) [E] [mailto:srosenzweig at cc.nih.gov] 

> Lähetetty: 13. toukokuuta 2014 15:13

> Vastaanottaja: Seppänen Mikko; 'Juan Carlos Aldave Becerra'

> Aihe: Re: Peruvian 10-yr-old girl with novel PIDD?

> 

> Thanks Mikko!

> Hi Juan Carlos,

> As Kate suggested, dyskeratosis congenita-Hoyeraal-Hreidarsson variant (RTEL1 and DKC1 mutations) rank high on my differential. The other thing I'd be concerned is radio sensitivity (always a matter to be scared of with the neuro-immune-bone marrow syndromes as Lig4). Unfortunately we cannot "pick up the the bill" this time, but telomere length could be sent to a commercial lab in Canada for a fee, and would help to define if DC is a possible diagnosis and it will also have clinical impact if your are planing HSCT to define conditioning regimen

> We keep in touch,

> Sergio

> 

> Sergio D. Rosenzweig, MD, PhD

> Director, Primary Immunodeficiency Clinic (PID-C)

> LHD, NIAID, NIH

> 10 Center Dr, Bldg. 10, Rm. 2C410F

> Bethesda, MD, 20892

> Phone (301) 451 8971

> Fax (301) 402 1884

> Cell (240) 361 7617

> Pager 102 10678

> srosenzweig at cc.nih.gov<mailto:srosenzweig at cc.nih.gov>

> 

> Disclaimer: The information in this e-mail and any of its attachments is confidential and may contain sensitive information. It should not be used by anyone who is not the original intended recipient. If you have received this e-mail in error please inform the sender and delete from your mailbox or any other storage devices. National Institutes of Health shall not accept liability for any statements made that are senders own and not expressly made on behalf of the NIH by one of its representatives.

> From: Seppänen Mikko <Mikko.Seppanen at hus.fi<mailto:Mikko.Seppanen at hus.fi>>

> Date: Tuesday, May 13, 2014 4:14 AM

> To: 'Juan Carlos Aldave Becerra' <jucapul_84 at hotmail.com<mailto:jucapul_84 at hotmail.com>>

> Cc: srosenzweig <srosenzweig at cc.nih.gov<mailto:srosenzweig at cc.nih.gov>>

> Subject: Peruvian 10-yr-old girl with novel PIDD?

> 

> Dear Juan,

> (CC Sergio)

> 

> You have a truly unique case in Peru!

> 

> The reason I did not respond is that-  in my opinion - this is not a known gene defect/phenotype. The fluctuating myelodysplasia is extremely interesting....

> Nima Rezaei has recently published an excellent review on neurologic diseases and PIDD, since then at least PGM3, MOGS, IFIH1 should be added to the list. You might want to peruse these through? Let me know if You have no access to them.

> 

> I was kind of hoping that someone would contact You privately and suggest exome/genome sequencing... It is always tough with one patient and it gets tougher even if a good candidate is found, since functional testing requires fresh samples. Thus I was not eager to recruit into our WES/WGS projects... Someone from the Americas should do it...?

> 

> Considering places where there would be resources to hunt this, I would ask either

> USA, for example Sergio srosenzweig at cc.nih.gov<mailto:srosenzweig at cc.nih.gov> or Gulbu guzel at niaid.nih.gov<mailto:guzel at niaid.nih.gov>  in NIH,

> or Brazil, for example Dewton dmvascon at usp.br<mailto:dmvascon at usp.br>

> 

> Since somehow this IMHO would best fit Sergio's and Steve's interests (?), I will fwd this to Sergio. If the State of Peru could send the patient for evaluation into the NIH hospital, this would be very much doable...? If I remember correctly, flight tickets for the mother and daughter would be what it would cost???

> 

> Sorry I cannot be of more help at this stage, I REALLY do hope someone picks studies on her up! She has a story to tell! Treatment-wise her case is even tougher.... :=((

> 

> With best wishes,

> 

> Mikko

> 

> Lähettäjä: Juan Carlos Aldave Becerra [mailto:jucapul_84 at hotmail.com]

> Lähetetty: 13. toukokuuta 2014 6:17

> Vastaanottaja: Seppänen Mikko

> Aihe: FW: Peruvian 10-yr-old girl with recurrent severe pancytopenia, and physical/mental retardation

> 

> Dear Dr Seppanen,

> 

> I am Juan, from Peru. I posted this case in the CIS PID list some days ago but, except for Dr Kate Sullivan, I have not received any response, so I turn to your expertise to get some help.

> I evaluated this week a 10 yr-old girl with a very puzzling clinical picture. I describe below the clinical history (also attached in a word file).

> 

> The main features are:

> - Recurrent severe pancytopenia, predominantly of the myeloerythroid lineage.

> - Physical and mental retardation with cerebral atrophy and microcephaly.

> - Residual bronchiectasis

> 

> I would appreciate your expert insights and suggestions.

> Thank you very much.

> 

> We have another STAT1 GOF patient! (Dr. Puel sent me the result about 3 weeks ago).

> 

> Sincerely,

> 

> Juan Carlos Aldave, MD

> Allergy and Clinical Immunology

> Hospital Nacional Edgardo Rebagliati Martins

> Lima, Peru

> 

> -----------------------------

> Girl, 10 yrs of age

> Date of birth: August 11th 2004

> 

> FAMILY HISTORY:

> -       No family members with suspicion of PID.

> -       No siblings, healthy parents (50 and 51 yrs of age).

> -       The maternal 1st grade female cousin of the patient's mother died due to "aplastic bone marrow".

> -       No consanguinity.

> 

> PERSONAL HISTORY:

> -       Intrauterine growth retardation

> -       Weight at birth=1,720 g (gestational age=7.5 months)

> -       No adverse reactions to live vaccines, including BCG

> -       Current weight=18 kg (below P3 for age)

> -       Current height=114 cm (below P3 for age)

> -       Local adverse reactions to mosquito bites.

> 

> CURRENT DISEASE:

> -       Apparently healthy up to 11 months of age.

> 

> -       From 11 months of age: recurrent episodes of severe thrombocytopenia (up to less than 1,000 platelets/?L), neutropenia (up to less than 100 neutrophils/?L) and anemia (up to 6 g/dL, low reticulocyte counts); in some episodes there also was mild-moderate lymphopenia (~1,000 lymphocytes/?L). Please see the table below for detailed CBCs during some episodes).

> ·      Duration of the episodes: 3 to 4 weeks, and resolve spontaneously.

> ·      Frequency of the episodes: every 7 to 21 months.

> ·      Total number of episodes in the patient's life: twelve (February 2005, September 2005, April 2006, December 2006, September 2008, February 2010, September 2010, July 2011, November 2012, July 2013 [only thrombocytopenia], October 2013 [only neutropenia], the last episode started 2 weeks ago).

> ·      Clinical features during the episodes:

> .  Total alopecia (hair grows again after the episodes), high fever, vomiting, hiporexia, diarrhea, petechiae, mucosal bleeding, oral candidiasis, elevated ESR (~40 mm/h).

> .  Parents note that despite all these clinical features the patient does not appear acutely ill during the episodes.

> .  No lymphadenopathies, no hepatosplenomegaly

> ·      Response to therapies:

> .  No response to G-CSF and IVIG.

> .  Patient was treated with high-dose systemic corticosteroids during the episode of November 2012 and the father noticed that there was good response (the episode lasted shorter).

> ·      Complications during the episodes:

> .  'Bacterial' pneumonia (no microorganisms were isolates) during the episode of April 2006, complicated with pleural effusion and residual bronchiectasis.

> .  Pneumonia, positive blood culture to Pseudomona aeruginosa.

> 

> -       Between episodes the patient has not had any severe or opportunistic infection.

> -       Bronchiectasis from 2 yrs 6 months of age, persistent production of sputum.

> -       Growth and mental retardation that was noticed at the first episode of pancytopenia (11 months of age). Example: she walked at 4 years of age. Current neurological and physical development appears as from a 6-yr-old child.

> -       Microcephaly.

> -       Apparently normal facies.

> 

> WORK UP:

> 

> CBC counts at birth and during the 1st episode

> 

> 

> 

> 13-3-2004

> 

> 12-2-2005

> 

> 14-2-2005

> 

> 16-2-2005

> 

> 18-2-2005

> 

> 20-2-2005

> 

> 

> 

> 2 days of age

> 

> 1st episode of thrombocytopenia, neutropenia and anemia

> 

> Platelets (per ?L)

> 

> 200,000

> 

> 68,200

> 

> 60,500

> 

> 117,000

> 

> 275,000

> 

> 412,000

> 

> Hemoglobin

> 

> 17.1

> 

> 6.8

> 

> 11.9

> 

> 12

> 

> 12.9

> 

> 13.7

> 

> WBC

> 

> 9,800

> 

> 4,900

> 

> 8,340

> 

> 6,350

> 

> 11,700

> 

> 10,400

> 

> Neutrophils

> 

> 45%

> 

> 2%

> 

> 5%

> 

> 10%

> 

> 27%

> 

> 8%

> 

> Banded

> 

> 1%

> 

> 0%

> 

> 1%

> 

> 3%

> 

> 8%

> 

> 2%

> 

> Lymphs

> 

> 44%

> 

> 94%

> 

> 85%

> 

> 68%

> 

> 50%

> 

> 77%

> 

> Eosinophils

> 

> 1%

> 

> 4%

> 

> 4%

> 

> 0%

> 

> 2%

> 

> 1%

> 

> Basophils

> 

> 1%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> Monocytes

> 

> 8%

> 

> 0%

> 

> 5%

> 

> 18%

> 

> 12%

> 

> 12%

> 

> 

> CBC counts during the 2nd and 3rd episodes

> 

> 

> 

> 14-9-2005

> 

> 15-9-2005

> 

> 06-4-2006

> 

> 10-4-2006

> 

> 22-4-2006

> 

> 29-4-2006

> 

> 

> 

> 2nd episode

> 

> 3rd episode

> 

> Platelets (per ?L)

> 

> 18,600

> 

> 106,000

> 

> 4,000

> 

> 15,000

> 

> 14,000

> 

> 250,000

> 

> Hemoglobin

> 

> 10.1

> 

> 9.7

> 

> 7.2

> 

> NA

> 

> 9

> 

> 11. 1

> 

> WBC

> 

> 2,540

> 

> 2,190

> 

> 1,000

> 

> 800

> 

> 4,500

> 

> 19,200

> 

> Neutrophils

> 

> 3%

> 

> 1%

> 

> 0%

> 

> 0%

> 

> 29%

> 

> 46%

> 

> Banded

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 12%

> 

> 16%

> 

> Lymphs

> 

> 87%

> 

> 95%

> 

> 96%

> 

> 49%

> 

> 46%

> 

> 27%

> 

> Eosinophils

> 

> 0%

> 

> 4%

> 

> 3%

> 

> 0%

> 

> 1%

> 

> 0%

> 

> Basophils

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> Monocytes

> 

> 6%

> 

> 0%

> 

> 0%

> 

> 0%

> 

> 10%

> 

> 2%

> 

> 

> Immunologic testing (during an episode):

> -       July 27, 2011: IgG=1127, IgA=137, IgM=127 mg/dL, IgE=506 UI/mL

> 

> Immunologic testing (between episodes):

> -       May 31, 2006: IgG=2052, IgA=119, IgM=162 mg/dL, IgE=62 UI/mL

> -       September 19, 2007: IgG=980, IgA=68, IgM=71 mg/dL, IgE=62 UI/mL

> -       May 31, 2006: CD3+ cells=14,028 (68% HLA-DR +); CD4+ T cells=2,304; CD8+ T cells=10,688; CD19+ cells=450.

> -       August 28, 2007: WBC=6,300; lymphs=4,095; CD3+ cells=2,079 (most HLA-DR and CD25 negative); CD4+ T cells=1,134; CD8+ T cells=882; CD19+ cells=1010; CD56+ cells= 378/mm3.

> -       Negative autoantibody panel (ANA, anti-DNA, ANCA, anti-Sm, anti-RNP, anti-SS-A, anti-SS-B, anticardiolipin, lupus anticoagulant).

> -       C3 and C4 complement proteins: normal levels.

> 

> Infectious disease testing:

> -       Negative testing for acute EBV, CMV, parvovirus B19, herpes simplex, toxoplasma, Salmonella typhi and Brucella sp infection.

> -       Negative testing for viral hepatitis.

> -       Negative RPR.

> 

> Hematologic testing:

> -       Reticulocyte count <1.5%.

> -       Haptoglobin=344 mg/dL (normal levels: 30-200).

> -       LDH=662 mg/dL (normal levels: 58-158).

> -       Serum iron=318 mg/dL (normal levels: 58-158).

> -       Serum transferrin=118 mg/dL (normal levels: 250-400).

> 

> Genetic and metabolic testing:

> -       Serum glucose, urea, creatinine, transaminases, albumin and electrolyte levels: within normal limits

> -       Ferritin >1,500 mg/dL

> -       Normal newborn screening tests for hypothyroidism and phenylketonuria.

> -       Karyotype: normal 46,XX

> -       Diepoxybutane (DEB) test: no chromosomal breakages.

> -       No detection of urinary abnormal metabolites.

> -       Aminoacid chromatography: normal

> 

> Histology results:

> -       Bone marrow smear (during an episode; 20/9/2005): severe bone marrow hypoplasia (lymphocytes=62%).

> -       Bone marrow smear (during an episode; 22/9/2005): reduced myeloerythroid lineage.

> -       Bone marrow smear (between episodes; 25/5/2006): reactive bone marrow.

> -       Bone marrow biopsy (between episodes; 25/5/2006): normal findings.

> 

> Imaging results:

> -       Brain US (23-3-2004): no abnormalities.

> -       Brain CT (03-9-2004): bilateral frontoparietal cortical atrophy.

> -       Brain MRI (14-9-2004): dysplastic cranium; retardation of myelination; hypoplastic or developing brain.

> -       Chest CT (12-5-2006): inflammatory process in the parenchyma of the left lung base; loculated pneumothorax; consolidation in the right lung base.

> -       Large bone and crania X-rays: normal.

> 

> DIAGNOSIS:

> -       Recurrent severe pancytopenia, predominantly of the myeloerythroid lineage.

> -       Physical and mental retardation with cerebral atrophy and microcephaly.

> -       Bronchiectasis

 		 	   		  
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