IPEX (Immunodysregulation, Polyendocrinopathy,Enteropathy, X-linked)

IPEX is a very rare syndrome marked by aggressive autoimmunity and usually - but not invariably - results in early death. Since the condition is X-linked, only males are affected. It is due to mutations in FOXP3, a key transcription factor for regulatory T cells, and work with a mouse model known as scurfy has confirmed that immune hyper-reactivity results from a lack of functional regulatory T cells. Clinical features are highly variable and include early onset type 1 diabetes, hypothyroidism, severe enteropathy, eczema, anaemia and thrombocytopenia. Haemopoietic stem cell transplantation has sometimes been effective in its treatment.

Introduction

IPEX was first described in 1982 as an X-linked disorder characterized by diarrhoea, polyendocrinopathy, infection and early death, affecting 19 males across 5 generations[1].

A total of 136 cases had been reported by 2012, but diagnosis has become more frequent as paediatrician become more aware of the condition. Wide genotypic/phenotypic variation has been described.[2]

Clinical Features

A family history of early male neonatal death may easily be missed, and birthweight is usually normal. The condition manifests within weeks or months as a triad of:

  • Intractable diarrhoea
  • Type 1 diabetes
  • Eczema

Severe enteropathy with watery or bloody diarrhoea may begin during breast feeding (and is thus unrelated to dietary gluten); parenteral feeding is usually needed for survival.

Type 1 diabetes often develops within days of birth and can be very hard to control with insulin

Children who survive the neonatal period are subject to a widening spectrum of other immune manifestations affecting the thyroid, blood components, liver or kidneys.

Genetics

Forkhead box p3 is a master regulator for the function of thymic-derived regulatory T cells. The corresponding cells are present in normal quantities in IPEX but do not function effectively[3].

The mutations usually affect regions of the transcription factor which are required for binding to regulatory cell DNA

Biochemical Features

These are dominated by the features of protein-losing enteropathy, but raised IgE and eosinophilia are characteristic.

Immunodeficiency

May be related to hyper-reactivity of the infant's own immune system or to graft-versus-host disease due to maternal lymphocytes.

Clinical management

*George:  recipient of a stem cell transplant for IPEX in Newcastle
*George: recipient of a stem cell transplant for IPEX in Newcastle
Management is supportive with fluid and nutritional replacement usually supplemented with antibiotics. Steroids and/or immunosuppression are often added.

Haemopoietic stem cell transplantation has been attempted in 28 patients, but only three are known to have survived more than 8 years.

*See news item on George Young

References

  1. ^ Powell BR et al, An X-linked syndrome of diarrhoea, polyendocrinopathy and fatal infection in infancy. J Pediatr 1982;100:731-7

  2. ^ Barzaghi F et al. IPEX: a paradigm of immunodeficiency with autoimmunity. Frontiers in Immunology 2012;31 July 2012

  3. ^ Michels AW, Gottlieb P. Autoimmune polyendocrine syndromes. Nat Rev Endocrinol 2010;6:270-77

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