NEMO Deficiency Syndrome

NEMO deficiency syndrome is an X-linked disorder from variants in IKBKG (NEMO) that disturb NF-kappa-B activation. Hypomorphic variants in males cause ectodermal dysplasia with immunodeficiency, and null variants in females cause incontinentia pigmenti.

Pathophysiology. NEMO is the regulatory subunit of the IKK complex needed for NF-kappa-B signalling from Toll like receptors, IL-1 receptors, TNF receptor, CD40 and ectodysplasin receptor. Hypomorphic variants in boys impair immunity and ectodermal development, while complete loss is lethal in males.

In boys, onset is in infancy. In girls with incontinentia pigmenti, the skin phase starts at birth, and severity depends on skewed X inactivation.

Complications are severe infection, colitis and, in girls, retinal and neurological disease.

• Males, immunodeficiency: recurrent pyogenic infection (pneumococcus, Staphylococcus aureus, Haemophilus), mycobacterial infection, CMV and other viral infection, Pneumocystis
• Males, ectodermal features: sparse fine hair, conical or missing teeth, hypohidrosis or anhidrosis, frontal bossing, heat intolerance and unexplained fever in warm places
• Chronic colitis and failure to thrive
• Lymphoedema and osteopetrosis in a few
• Females, incontinentia pigmenti: linear blistering rash in the first weeks, then warty lesions, swirled hyperpigmentation and pale scarring; dental anomalies, alopecia, retinal vascular disease, seizures and developmental delay

• Immunoglobulins: variable, with low IgG and IgA and normal or high IgM, and poor responses to polysaccharide vaccines.
• Lymphocyte subsets: usually normal numbers, with low memory B cells.
• NK cell cytotoxicity: reduced.
• Functional tests: impaired cytokine response to TLR agonists, IL-1 beta, TNF and CD40.
• Genetic testing of IKBKG (including common exon 4 to 10 deletion testing for incontinentia pigmenti), with maternal testing.
• Ectodermal assessment: dental X-ray, sweat testing, hair examination.
• Girls with incontinentia pigmenti: dilated retinal examination in the first months, and MRI brain with neurological signs.
• Colonoscopy and biopsy for chronic diarrhoea, and infection workup.

Differential diagnosis.

• Hypohidrotic ectodermal dysplasia without immunodeficiency (EDA, EDAR)
• IkB-alpha gain-of-function deficiency
• IRAK4 and MyD88 deficiency
• CD40 ligand deficiency and common variable immunodeficiency
• Mendelian susceptibility to mycobacterial disease
• Other causes of very early onset inflammatory bowel disease

• Immunoglobulin replacement for antibody failure: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Antibacterial prophylaxis: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily).
• Pneumocystis prophylaxis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Mycobacterial prophylaxis: azithromycin 10 mg/kg orally three times weekly in children (maximum 500 mg), 500 mg in adults, after ECG shows QTc under 450 ms.
• Early treatment of infection, often without fever: after cultures, ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g), then adjust to cultures.
• Colitis: exclude infection, then mesalazine, and immunosuppression under specialist direction. Avoid agents that deepen immunodeficiency without immunology advice.
• Heat care: cool environments, tepid sponging and fluids; hypohidrosis can cause hyperthermia, and unexplained fever may be heat illness.
• Dental care: early prosthetic teeth and regular review. Use artificial tears and wigs or hair care as needed.
• Incontinentia pigmenti: ophthalmology review every 1 to 3 months in infancy for retinal disease, with laser or cryotherapy for neovascularisation, and neurology input.
• Haematopoietic stem cell transplantation is considered for severe immunodeficiency, but graft failure and colitis complications are frequent, so transplant at an experienced centre.
• Vaccines: inactivated only; no BCG or live vaccines.

Special groups.

• Mothers: carrier testing and genetic counselling, because each son has a 50% chance of being affected and each daughter a 50% chance of carrying the variant.
• Girls with incontinentia pigmenti: monitor skin, eyes, teeth and neurology through childhood.

Monitoring. Trough IgG every 3 months. Full blood count, liver enzymes and creatinine every 3 to 6 months. Growth and weight at each visit. Eye examinations every 1 to 3 months in infancy for girls with incontinentia pigmenti.

Referral and escalation. Refer to paediatric immunology and genetics. Emergency for sepsis, respiratory distress, heat illness or acute neurological change.