NEMO deficiency syndrome

Overview

In the chain of chemical reactions after TLR activation, NF-kappa-B essential modulator (NEMO) is an important protein downstream of Myd88 and IRAK-4. NEMO is required for the activation of the NF-kappa-B family of transcription factors. These factors ultimately regulate lymphocyte development and proliferation, inflammation, and immune responses. 

Besides TLRs, other signaling pathways also recruit NEMO. For this reason, in NEMO deficiency, many cellular processes are affected and individuals tend to have more clinical manifestations compared to TLR deficiencies. One of these pathways starts with the ectodysplasin-A receptor, which is important for the development of ectodermal tissues, such as hair, skin, and nails. Malfunction of this pathway results in anhidrotic ectodermal dysplasia (EDA), a condition characterized by dry and thickened skin, conical teeth, absence of sweat glands, and thin, sparse hair. Several different defects can cause EDA, but the association of EDA and immune defects (EDA-ID) is highly suggestive of NEMO deficiency. 

From the immunological standpoint, individuals with NEMO deficiency syndrome have a range of infections with pyogenic (pus-inducing) organisms. Streptococcus pneumoniae and Staphylococcus aureus are the most common pathogens, but individuals with NEMO can also have viral and fungal infections. Infections can be severe and may be found virtually anywhere in the body, including the lungs, skin, central nervous system, liver, abdomen, urinary tract, bones, and gastrointestinal tract. 

Many individuals have humoral immunity problems with a complete lack of antibody response against certain bacteria, such as pneumococcus, despite vaccination. A subset of these individuals presents with high serum levels of IgM. Other individuals exhibit defects in additional arms of the immune system that cause increased susceptibility to mycobacteria. These individuals may develop disseminated infection if they receive the BCG vaccine (the live vaccine against tuberculosis, which is commonly given in countries other than the U.S.).

About 90% of individuals with NEMO deficiency have EDA. A small group of individuals have a more severe disease course, presenting with two additional conditions: osteopetrosis (a disorder in which bones are denser, prone to fractures, and the bone marrow fails to produce blood cells) and lymphedema (fluid retention due to defects in lymphatic vessels), known as OL-EDA-ID syndrome.

NEMO deficiency is inherited in an X-linked manner; hence, almost all cases occur in boys. Female carriers are normally free of immune symptoms, but some might have a condition called incontinentia pigmenti, mostly affecting the skin.