[CIS PIDD] [cis-pidd] Microcephaly + telangiectasias + lymphopenia + SNC dysplasia + heterozygous NBN variant of unknown significance

[CIS-PIDD]

Dear all, greetings from Mexico.

I am seeing a (2yo boy) with history of skin and gastrointestinal symptoms
(atopic dermatitis + bloating + distention) that were classified as food
allergy and atopic dermatitis, and managed with several diet restrictions
and topical steroids/pimecrolimus. The skin seems to respond partially,
mainly because telangiectasias remain once inflammation has decreased (I
cannot tell if these changes are sequels of the topical steroids or part of
the underlying disease).

The patient also has intermittent respiratory symptoms involving the nose
and lungs (congestion, rhinorrea, sneezing, snoring, cough, without
wheezing). Respiratory symptoms have improved significantly with topical
treatment (nasal mometasone 400mcg/day and inhaled budesonide+formoterol
640mcg/18mcg/day, and then decreased and stayed at 200mcg/daý and
320mcg/9mcg/day respectively).

Allergy skin tests resulted positive for: casein 4mm, egg white 4mm,
english walnut 5mm, meat 6mm, Blomia tropicalis 6mm, standardized cat hair
4mm, red maple 4mm, latex 4mm, negative control (glycerine) 0mm, histamine
10mg/ml 15mm.

ImmunoCAP IgE (negative, <0.1 kU/L) for egg white, egg yolg, cow's milk,
wheat, and soybean.

I have managed him with restriction to egg, nuts, meat with good clinical
response.Because topical management has controlled well respiratory
symptoms I have not proceeded with allergen specific immunotherapy.

What puzzles me is that he has microcephaly, "birdlike" face with prominent
filtrum, bilateral facial telangiectasias (cheeks), and mild bilateral low
implantation of ears. His height and weight are normal (classified as
eutrophic). No other physical findings.

Because of the microcephaly (diagnosed in-utero, and always below the
percentile 3), he was first assessed by a paediatric neurologist resulting
in SNC dysplasia confirmed with MRI. Mild impact on his developmental
milestones without compromise on motor skills and no other neurological
manifestation.

A NGS gene-panel for syndromatic microcephaly revealed: three unknown
significance variants for ARFGEF2 c.172C>T, for VPS13B c.7753G>A, and for
NBN c.425A>G.

Lab work-up:

Abnormal blood count with mild increment in RDW, mild relative and absolute
lymphopenia
(Hb 13 g/dL Ht 38% MCV 76.7 fL, MHC 26.2 pg, MCHC 34.2 g/dL, RDW 15.2% WBC
6,400, ANC 4,100/mcl (63.5%), lymphocytes 1,600/mcl (24.3%), monocytes
700/mcl (10.7%), eosinophiles 100 (1.2%), basophiles 0 (0.3%), platelets
250,000/mcl, MPV 8.4fL)

Abnormal lymphocyte subsets:

Absolute lymphocytes 1,663 / mcl
B cells - CD19+ 224 / mcl
T cells - CD3+ 1,319 / mcl
T helper - CD3+CD4+ 630 / mcl
T cytotoxic - CD3+CD8+ 617 / mcl
Ratio of CD4+/CD8+ 1.0
NK cells - CD3-CD16/56+ 104 / mcl

Normal 46,XY karyotype (cells were able to grow on the culture).
Normal C3, C4, IgA 67 mg/dL, IgG 632 mg/dL, IgM 72mg/dL, IgE 25 UI/L
Blood type O concordant with anti-A and anti-B isohemaglutinines 1:32 each.
Normal Streptococcus pneumoniae IgG titers - 13/23 (56%) > 1.3mcg/ml
Normal tetanus and diphtheria IgG titers

Frankly because of microcephaly, telangiectasias and lymphopenia I
considered NBS as a possibility, but with VUS in heterozygous state, and a
normal karyotype it became difficult to make a diagnosis. Together with the
geneticist we sequenced (NGS) both parents for such variants, and found
them as carriers of the three mutations (two in the father and one in the
mother), without any kind of symptoms/signs of disease.

So I am puzzled and asking for your help. How should I give follow-up?
Should I have a high index of suspicion for malignancy everytime I see him?
for how long? what kind of tests should I ask for, and how frequently? I
have been thinking in assessing for radiosensitivity with the bleomycin
test. He has an older healthy brother, should I assess HLA for future
decisions?

I would really appreciate your comments.

Thank you and best regards,
-
Dr. Armando Partida Gaytán
dr.partida.g at gmail.com
www.aeicp.com
www.kidshealthpolanco.com
________________________
Co-editor
Acta Pediátrica de México
Instituto Nacional de Pediatría
www.actapediatrica.org.mx
_______________________
Pediatría y Alergia e Inmunología Clínica Pediátrica
Hospital Infantil de México Federico Gómez
Inmunodeficiencias primarias
Instituto Nacional de Pediatría
Maestría en Ciencias Médicas
Universidad Nacional Autónoma de México
Maestría en Terapia Génica y Celular
University College London Great Ormond Street Institute of Child Health

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