ARTICLE
Auteur(s) : E
Puzenat1, P Rohrlich2, P
Thierry3, P Girardin1, M Taghian3,
M Ouachee4, E Plouvier2, A
Fischer4, P Humbert1, F Aubin1
1Dpt of Dermatology, University Hospital, 25030
Besançon cedex, France
2Dpt of Pediatrics, Bone Marrow Transplantation Unit,
University Hospital, Besançon, France
3Dpt of Pediatrics, General Hospital, Vesoul, France
4Dpt of Pediatric Immuno-hematology,
Necker-Enfants-Malades University Hospital, Paris, France
accepté le 15 Novembre 2006
Omenn syndrome (OS) is a severe combined immunodeficiency (SCID)
associated with early-onset generalized, exsudative erythroderma,
lymphadenopathy, hepato- and splenomegaly, hypereosinophilia,
hypogammaglobulinemia and elevated serum IgE. Most cases are due to
autosomal recessive inherited mutations in the recombination
activating genes RAG1 or RAG2, resulting in the absence of
circulating B cells and non-functional oligoclonal T cells. We
report a new case of OS occurring in a newborn with RAG 1
mutations, who benefited from a bone marrow transplantation.
Case report
A 3 day-old boy, who was the second child born to
non-consanguineous parents. Diffuse exfoliative erythroderma with
hair loss was noted from birth (figures 1 and 2). At 4
weeks of age, erythroderma remained but he had no fever, no
organomegaly and no infection. Weight gain was normal. Initial
haematology was normal but severe lymphopenia (350/mm3)
with hypogammaglobulinemia and severe neutropenia
(600/mm3) appeared with an elevation of eosinophil count
at 5,000/mm3. His chest X ray showed thymus hypoplasia.
No cutaneous biopsy was performed.
An immunodeficiency seemed likely. Serum IgA was 0.07 g/L
(normal values: 0.49-2.44 g/L), IgG 1.09 g/L (2.08-12.11 g/L), IgM
0.17 g/L (0.49-1.62 g/L), with an increased IgE count (9 g/L). The
T lymphocyte population was oligoclonal at the TCR level, a
characteristic feature in OS. Materno-foetal graft versus host
disease was excuded by blood chimerism study.
The diagnosis of OS was then confirmed by the analysis of RAG 1
and RAG 2 genes on the genomic DNA of the patient and his parents.
Sequence analysis showed RAG1 mutations, del T2735 from his father,
and A3086G from his mother.
The child received an allogenic HLA-identical bone marrow
transplantation from his brother with no conditioning because of
the low risk of bone marrow rejection in this setting. The BMT was
followed by 6 months-cyclosporine treatment and polyvalent
immunoglobulin weekly substitution during 4 months. Engraftment was
confirmed and, 6 months later, weight gain was normal, erythroderma
had disappeared and he had no recurrent infection.
Discussion
OS is an autosomal recessive form of severe combined
immunodeficiency (SCID). The male to female ratio is about 1. In
general, the children develop symptoms before the age of 8 weeks.
80% of the children present erythroderma, hepatosplenomegaly and
lymphadenopathy. During the course of the disease, they can also
develop alopecia, chronic diarrhoea, failure to thrive and
recurrent infection [1, 2]. Without treatment, patients die of
infections and severe metabolic disturbances within the first
months of life.
A proportion of OS cases are due to autosomal recessive
inherited mutations in the recombination activating genes RAG1 or
RAG2, which mediate the process of V(D)J (Variable, Diversity,
Joining) recombination. Recently, other studies suggested that
defects in genes other than RAG may cause OS, with a phenotype
indistinguishable from that due to RAG mutations. Mutations in the
Artemis gene, IL7RA mutations and mutations in the Rnase
mitochondrial RNA processing RNA gene [3-6] are described. The
physiopathogeny of OS in case of RAG mutations was recently
elucidated by Villa et al. [7]. They demonstrated mutations in RAG1
and RAG2 genes resulting in defects in the activity of RAG1 and
RAG2 enzymes. Normally, RAG1 and RAG2 proteins, which are
restricted to immature lymphocytes, initiate a V(D)J recombination.
This recombination leads to both T and B cell development. Absence
of V(D)J recombination results in severe combined immunodeficiency
such as OS [8-10]. In OS, the V(D)J recombination is partial and
characterized by the absence of circulating B cells, with only a
small number of T cell clones. The activated oligoclonal T
lymphocytes infiltrate the skin, the gut, the liver and the spleen
leading to clinical manifestations. The number of peripheral blood
lymphocytes can be decreased, normal or elevated with no or
strongly decreased B cells and hypogammaglobulinaemia.
Hypereosinophilia and elevated IgE levels are usually found
[2].
We strongly suspected OS because of the severe erythroderma in
combination with immune abnormalities, although it was remarkable
that neither failure to thrive nor organomegaly or infection
occurred in our patient. In addition, despite the lack of
conditioning, the bone marrow transplantation was successful.
Neonatal erythrodermas are rare. Pruszkowski et al. conducted a
retrospective study of 51 cases of neonatal erythroderma [11]. In
their analysis, the leading causes of neonatal erythroderma were
immunodeficiency (30%), simple or complex ichthyosis (24%), and
Netherton’s syndrome (18%). Atopic dermatitis and seborrheic
dermatitis were less frequent. They concluded that immunodeficiency
(OS, severe combined immunodeficiency, graft-vs-host disease
(GVHD), Ig A deficiency and Wiskott Aldrich’s syndrome) should be
suspected in cases of severe neonatal erythroderma with failure to
thrive and recurrent infections. In some circumstances,
histological examinations may be helpful. Scheimberg et al.
reviewed skin biopsies from 25 patients with graft-vs-host
diseases, OS and Netherton’s syndrome. In their study, histological
examinations of patient with OS always showed acanthosis, sometimes
associated with parakeratosis and dermal lymphocytic infiltration
[12]. In OS, blood examination and skin biopsies never show
infiltrating maternal T cells, which are typical of materno-fetal
GVHD [13]. However, histological findings are often non specific
before 6 weeks of age and the biopsy must be repeated. Prenatal
diagnosis of OS caused by RAG mutations can be performed with
molecular diagnostic procedures in families previously affected
[14]. OS is fatal if untreated; the most frequent causes of death
are recurrent infections, particularly respiratory infections and
septicaemia. Early recognition of the disease is required to
initiate appropriate treatment. HLA identical or haploidentical
bone marrow transplantation or cord blood stem cell transplantation
can cure OS. In patients who lack a histocompatible sibling, the
use of unrelated donors is not so successful as in other forms of
SCID [15, 16]. The sepsis complications and the risk of
post-transplant rejection are higher in OS compared to patients
with other types of SCID [16, 17].
Primary immunodeficiency diseases are rare in children.
Cutaneous alterations may precede the clinical immunologic
diagnosis as diagnostic markers [18]. The association of
erythroderma, lymphadenopathy, hepatomegaly with low
immunoglobulins and disseminated infection in a newborn is strongly
suggestive of immunodeficiency. However, our observation
demonstrates that immunodeficiency must be excluded in every case
of neonatal erythroderma, even in the absence of systemic
manifestation.
Acknowledgements
Financial support: none. Conflict of interest: none.
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