Identify the immunodeficiency

May 2007

A 9-year-old boy presented to our hospital for evaluation of primary immune deficiency. He was a full-term baby who, at 4 months of age, was hospitalized for respiratory syncytial virus pneumonia; no intubation was necessary. From that point until 2 years of age, he had multiple courses of antibiotics for pneumonia, but was not hospitalized.

At 2 years of age, the patient was hospitalized for a severe necrotizing pneumococcal pneumonia that did not respond to antimicrobials, which led to a partial resection of his right upper lobe. From age 2 to 5 years, he had multiple hospitalizations for pneumonia and lymphadenitis. At age 5, a bronchoscopy for persistent infiltrates grew Mycobacterium avium complex (MAC). The patient was treated with clarithromycin and rifampin with good response for nine months, but one year later lymphadenopathy and hepatosplenomegaly developed. Lymph node biopsy grew MAC.

Antimicrobials were broadened to include rifampin, moxifloxacin, ethambutol and clofazimine. Soon after, the patient developed a small bowel obstruction, which was also culture positive for MAC.

For the next several years until his visit with us, the patient had several flares of the lymphadenitis requiring drainage procedures, as well as intermittent fever, night sweats, weakness and weight loss. About a month prior to his admission at our hospital, he had a splenectomy for severe progressive hepatosplenomegaly and a gastrostomy tube was placed.

Increasing symptoms

At home during the weeks prior to his admission, the patient had increased abdominal girth, jaundice, fatigue and frequent bloody diarrhea. However, the fevers and night sweats abated some.

The patient’s family history was non-contributory.

He had two older brothers and a younger sister, all of whom were healthy. His development had been normal, but in recent years, the patient had missed significant amounts of school. They had been worried about his teeth and had seen the dentist, who felt that orthodontic work would be needed in the future.

On admission, he was cachectic and in respiratory distress with tachypnea (respiratory rate up to the 50 s/min.) and hypoxemia requiring admission to the intensive care unit. He had retractions and decreased breath sounds, but no crackles were auscultated.

Source: Alexandra F. Freeman, MD, and Steven M. Holland, MD

Hepatomegaly extended to his pelvis with ascites. The morphology and spacing of his teeth were abnormal (Figures 1 and 2), and the whorl of his hair was displaced to one side (see answer). His mother reported that they had a pet name for him of “sharktooth” because of his funny teeth, and that his hair had always been unruly.

Physicians had not commented previously about his tooth and hair abnormalities.

The patient’s chest computed tomography was remarkable for hazy, diffuse nodular infiltrates with several areas of denser consolidation.

Bronchoscopy was performed, and from bronchoalveolar lavage grew Alcaligenes xylosoxidans and Mycobacterium avium complex. Pneumocystis jiroveci was detected by fluorescent antibody.

The patient’s mycobacterial blood culture was positive for Mycobacterium avium complex.

Based on this history, the most likely diagnosis is:

1. Interferon-gamma receptor mutation
2. Nuclear factor kappa B essential modulator mutation (NEMO)
3. Hyper immunoglobulin E recurrent infection (Job’s) syndrome
4. Leukocyte adhesion deficiency-1 (LAD-1)

Answer

The correct answer is B, Nuclear factor kappa B essential modulator mutation, a rare X-linked disorder that many readers may not have heard of, but is underdiagnosed.

Mutations in NF-kappa B essential modulator mutation (NEMO) cause an immune deficiency characterized by a broad range of pathogen susceptibility that is frequently associated with ectodermal dysplasia. This boy is classic for this rare disease with his severe infections from bacteria (pneumococcus), viruses (RSV), mycobacteria and Pneumocystis, as well as his abnormal teeth and hair whorl.

Source: Alexandra F. Freeman, MD, and Steven M. Holland, MD

Mycobacterial infections are often particularly troublesome for these patients, and for this patient eventually led to his death. Signaling through toll-like receptors, essential components of innate immunity, utilizes NEMO and explains in part the broad range of infection susceptibility in these patients. Immunoglobulins can be helpful in diagnosing NEMO, but results are variable. Presentation as a hyper IgM syndrome with low IgG may be seen; NEMO is X-linked like another hyper IgM syndrome, CD40 ligand deficiency.

This patient’s IgM was quite elevated at 1,400 mg/dL (normal, 34 mg/dL to 342 mg/dL), but his other immunoglobulins were normal to elevated, as well; IgG was 1,410 mg/dL (normal, 642 mg/dL to 1,730 mg/dL), and IgA was 677 mg/dL (normal, 91 mg/dL to 499 mg/dL).

The ectodermal dysplasia can be variable; our patient had the classic conical, sparse teeth and abnormal hair whorl. Other features that may be seen are poor or absent sweating, sparse hair, pale skin and frontal bossing.

Making the diagnosis

Source: Alexandra F. Freeman, MD, and Steven M. Holland, MD

It is important to have a low threshold for considering NEMO mutations in boys with recurrent infections that are not clearly explained. Because there are hypomorphic mutations, the clinical phenotype (including the severity and types of infection) is quite variable. Diagnosis is through sequencing of NEMO. Therapy consists primarily of antimicrobial prophylaxis and consideration of immunoglobulin therapy. Stem cell transplantation has been successful.

As for the other choices, it is important to think of interferon (IFN)-gamma receptor defects in patients with disseminated mycobacterial infection. These defects can be inherited in a recessive or dominant manner, with the recessive disease having a much more severe phenotype. However, the broad range of infections as seen in this patient is not typical of IFN-gamma receptor defects, in which the infections are more limited to mycobacteria and salmonella, and ectodermal dysplasia is not seen. Patients with Job’s syndrome can have pulmonary mycobacterial infections as well as Pneumocytis carinii pneumonia, but the mycobacteria infection is limited to the lung, and the other associated features are different. Whereas in NEMO mutations, the teeth are sparse and conical, in Job’s syndrome, the primary teeth are retained. Leukocyte adhesion deficiency-1 (LAD-1) was included because there are also dental abnormalities; severe gingivitis can lead to tooth loss.

For more information:

• For more information about patients with disseminated or difficult mycobacterial infection, contact the authors at freemaal@mail.nih.gov or smh@nih.gov.
• Orange JS, Jain A, et al. The presentation and natural history of immunodeficiency caused by nuclear factor kappa B essential modulator mutation. J Allergy Clin Immunol. 2004;113: 725-733.
• Uzel G. The range of defects associated with nuclear factor kappaB essential modulator. Cur Opin Allergy Clin Immunol. 2005 5:513-518.