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.
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.
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.
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
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.
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.
The mutations usually affect regions of the transcription factor which are required for binding to regulatory cell DNA
These are dominated by the features of protein-losing enteropathy, but raised IgE and eosinophilia are characteristic.
May be related to hyper-reactivity of the infant's own immune system or to graft-versus-host disease due to maternal lymphocytes.
*George: recipient of a stem cell transplant for IPEX in NewcastleManagement 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
^ Powell BR et al, An X-linked syndrome of diarrhoea, polyendocrinopathy and fatal infection in infancy. J Pediatr 1982;100:731-7
^ Barzaghi F et al. IPEX: a paradigm of immunodeficiency with autoimmunity. Frontiers in Immunology 2012;31 July 2012
^ Michels AW, Gottlieb P. Autoimmune polyendocrine syndromes. Nat Rev Endocrinol 2010;6:270-77