[CIS PIDD] Patient with filamin A deficiency

[Norton, Allison]

We have a difficult case that we need some help with.  She is a 2 month old ex 34 3/7wk female who upon birth developed respiratory failure and hypotension was intubated.  She was diagnosed with sepsis/meningitis shortly after birth, but culture negative.  She was placed on ECMO briefly and was found to have severe pulmonary hypotension and hypoplastic lung on biopsy, now on significant vent support, iNO, Flolan, dopa & sedation. Also of note, has significant hepatomegaly, interrupted IVC, and periventricular heterotopia.  Genetics returned positive for Filamin A mutation.



Immune work up so far:



Intermittent eosinophilia: 140- highest 5960; currently at 650

Thrombocytopenia

No neutropenia or ongoing refractory anemia; Monocytes normal or high

lymphopenia  230-2690 (highest at near birth), now 1340



IgG: 988---now 785

IgM:49---now 15

IgE: 12--now 12

IgA: 60--- now 8

(She had received FFP about 6 days prior to the first labs, second set were drawn one month after last administration of FFP)



CD3:38  CD3#:353  CD4%30  CD4# 279  CD8/3%: 31  CD8/3# 316  CD56+16% 44 CD56+16# 449 CD19% <1



CD19# <10



ferritin 2505
Absent response to antigens, normal response to mitogens

TREC (sent to Mayo)
TREC copies 1311; CD3 384; CD4 326; CD8 147
CD4 RTE % 34.8 (normal 25-68)
CD 4 RTE absolute 108.5 (normal 170-10007)
CD20 absolute cells 0

Mayo T cell phenotyping
CD4+CD45RA+ naïve T cells 247
CD4+CD45RO+ memory cells 62
Interpretation: Modest increase in naïve, memory, and activated CD4+, CD8+ T cells, especially in the CD4+ memory T cell compartment of memory T cells.  While the proportion of overall CD45RA+CD8+T cells is normal for age, only 1/3rd of this population expresses CD62L- expressing naïve CD4 T cells is normal for age.  While there is an apparent increase in the frequency of CD4+ or CD8+ MHC class II expressing activated T cells, the proportion of CD4+25 dim is high for age at 35% of total CD4 T cells

Organic Acids- Urine: Highly elevated mevalonic acid suggesting mevalonate kinase deficiency

Genetics:
There is a large deletion on one of her X chromosomes
DNA sequencing revealed a c.6913_6943del31 in exon 43 of the FLNA gene.  This 31 nucleotide deletion will cause a frameshift and result in aberrant mRNA processing. This finding is consistent with a disease causing mutation. The patient is heterozygous for this mutation.

Periventricular heteroptopia, X-linked dominant, otopalatodigital syndrome, type I, otopalatodigital syndrome, type II, frontometaphyseal diysplasia, Melnick-Needles syndrome, cardiac valvular dystrophy, Xlinked, FG syndrome 2, and some documented cases of periventricular heterotopia, Ehlers-Danlos variant are X-linked mutations in the gene encoding for filamin A.

Exam does reveals head circumference <3%, appears dysmorphic, but no lymphadenopathy, liver down 9 cm, long fingers but no polydactyly, NO RASH or alopecia

A bone marrow biopsy has not been done yet.  SCID panel is pending.

So in summary:

This is a 2 month old female with history of meningitis, pulmonary hypoplasia requiring vent support, hepatomegaly, with Filamin A deficiency.  She has immunologic defects including eosinophilia, thrombocytopenia, lymphopenia, but evidence of some thymic output, absent response to antigens with intact response to mitogens, absent B cells (CD 19, CD20, absent in serum), normal for age but falling IgG, IgM, IgA, IgE.  She has a large deletion of her chromosome X, making X linked diseases possible.

There is no reported cases of immunologic defects with filamin A deficiency that I can find.  But filamin A is important for cell signaling, locomotion and does aid in immunological synapse formation (raft formation). Could I conceivably explain the absent T cell response to antigens with filamin A deficiency and some of her other immunologic derangements?  But I am not sure about the absent B cells with normal levels of immunoglobulins. I can not find cases of Brutons with normal IgM levels.  Do those exist?  Could this female patient have X linked Brutons and Filamin A deficiency?  Could I blame this all on filamin A deficiency?   Any thoughts would be helpful.



Allison Norton, MD
Assistant Professor
Pediatric Allergy & Immunology
Vanderbilt University

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