[PAGID] Diagnosis: Anaemia, Neutropenia, Immune deficiency and Vasculitis ?

[Nik-Zainal, Serena]

Dr Serena Nik-Zainal
Specialist Registrar in Clinical Genetics
Box 134
Clinical Genetics
Addenbrooke's Hospital NHS Trust
Hills Road
Cambridge CB2 2QQ
United Kingdom
Tel: 0044-1223-216446
Fax: 0044-1223-217054


-----Original Message-----
From: Mail Delivery System [mailto:Mailer-Daemon at relay.nhs.uk] 


Dear colleagues,

I would be very grateful for any advice/help with a diagnosis for this
family.

We have a family with a variable combination of neutropenia,  
anaemia, immunodeficiency and vasculitis, of three affected boys  
and one healthy and unaffected girl. There is no other family  
history.  Details of their medical histories are a little sketchy  
as these three boys have been managed in many different hospitals  
over the past 20 years, but I shall try to summarise what we do  
know about them.


CRH presented with a neonatal Hb of 3.3, MCV 89, normochromic with  
some poikilocytosis and anisocytosis. BM biopsy showed granulocytes  
at all stages, plasma cells and lymphocytes with normal morphology,  
no erythroblasts. Occasional megakaryocyte. Perhaps one or two  
histiocytes.  He required transfusions regularly and later  
developed a neutropenia in early childhood.  Igs were within normal  
limits. He had steroids which seemed to help the red cell aplasia  
to some extent. He had recurrent episodes of HSV infections and  
skin warts. Aged about 5, following a 2 day history of vomiting and  
diarrhoea, he collapsed at home and died.  PM was performed and  
showed a perianal ulcer, blotchy erythematous rash on upper legs,  
buttocks and abdomen, mass in the right iliac fossa comprising 4cm  
of terminal ileum and caecum. Caecal wall was necrotic. Cause of  
death given as septicaemia secondary to neutropenic enterocolitis.  
This was in 1986. Later, in 2003, when a younger brother developed  
intra-abdominal vasculitis, it was thought retrospectively that CRH  
had possibly had a bowel perforation from abdominal vasculitis.

They then had a girl JH (who is seeking genetic advice hence our involvement
in this family..as she is  now of child-bearing age) who is healthy and
well.


They then had another boy, CLH. He is also affected but presented  
with a mild-moderate neutropenia. Early in childhood, his immune  
system was investigated and this was normal. He has been followed  
up in Cambridge regularly and has not had too many in the way of  
problems.  However, when his younger brother presented with  
abdominal vasculitis, his immune status was investigated again  
because of a history of recurrent chest infections, and he was  
found to have marked hypogammaglobulinaemia and very low numbers of  
circulating B-cells, with a relatively low CD4+ count and a  
reverseCD4 to CD8 ratio. He has regular Ig infusions and is doing  
reasonably well.

The family then had another affected boy, KH. KH also presented  
with neutropenia early in life and a transient erythroblastopenia,  
which resolved after a few months. KH has had a more profound  
neutropenia than CLH, unresponsive to GCSF, tending to respond to  
prednisolone. Aged 12, he presented with angiographically confirmed  
intra-abdominal vasculitis resulting in a bowel perforation. At  
that point, he was completely neutropenic, with no neutrophil  
precursors in the marrow and he also had absent B-cells in the  
circulation with a marked hypogammaglobulinaemia. He has been  
managed with steroids and various immunosuppression agents, and has  
subsequently had a bone marrow transplant.

The boys are otherwise non-dysmorphic, and have normal neurological  
development. The pedigree would be consistent with an X-linked condition,
although we cannot rule out other modes of inheritance.
Mutation testing for Wiskott-Aldrich and neutrophil elastase (ELA2)  
has been performed in the past: no mutation detected.

I discussed the case with Prof Rusung Tan who suggested e-mailing PAGID. I
would be grateful for any suggestions as to a diagnosis.

Best wishes,
Serena

Dr Serena Nik-Zainal
Specialist Registrar in Clinical Genetics
Box 134
Clinical Genetics
Addenbrooke's Hospital NHS Trust
Hills Road
Cambridge CB2 2QQ
United Kingdom
Tel: 0044-1223-216446
Fax: 0044-1223-217054