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Case Challenges columnists present complicated pediatric case and explain how they came to a diagnosis.
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An 11-year-old Hispanic boy was referred to our hospital for evaluation of mucocutaneous candidiasis, failure to thrive, type 1 diabetes, secretory diarrhea and hemolytic anemia.
The patient had troubles since birth. He initially developed respiratory distress on his first day of life, which was attributed to a right hemidiaphragmatic paralysis. He had his first infection at age 10 days with an Escherichia coli urinary tract infection. At 6 months, he developed mucocutaneous candidiasis requiring maintenance fluconazole therapy, and had one episode of candidemia at age 3. A pneumonia at age 7 was smear and culture positive for Mycobacterium avium complex by bronchoscopy.
 Victoria Anderson |  Alexandra F. Freeman |
He had non-infectious manifestations starting at age 6. He was first diagnosed with hemolytic anemia responsive to steroids, and at age 10, he developed steroid-responsive pancytopenia. Type 1 diabetes was precipitated by the chronic steroid use. He developed severe, noninfectious diarrhea at age 6; he would have up to 27 stools a day. Upper and lower endoscopy revealed no goblet cells, small villi, and diffuse eosinophilia.
His physical exam at presentation to our hospital was notable for growth parameters below the fifth percentile for height and weight. His physical examination was remarkable for several facial features including macrencephaly, synophrys, long eyelashes, and hirsutism of the forehead and lateral aspects of the head, which were attributed in part to his chronic anti-inflammatory medications (including steroids and cyclosporine). He had midface hypoplasia with coarse features and hyperpigmentation of the nasal area. His skin was ichthyotic, and his finger and toenails were dystrophic from chronic candidal infections (figure 1). He had a Buffalo hump. The rest of his exam was significant only for coarse breath sounds and a systolic flow murmur. His chest CT scan showed evidence of bronchiectasis and scarring from previous pneumonias (figure 2).
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What laboratory tests would diagnose this boy’s immunologic disorder?
- Flow cytometry for interferon gamma receptor expression.
- AIRE gene mutation analysis for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).
- IgE for Hyper IgE (Job) Syndrome.
- FOX P3 mutational analysis for immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance syndrome (IPEX).
CASE DISCUSSION
The correct answer is D, immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance syndrome (IPEX).
This is a rare disorder and the case is very complicated with many systems involved, but it is worth thinking through the differential. His history was significant for many types of infections, with the mucocutaneous candidiasis giving him the most trouble, along with the various autoimmune manifestations and the severe diarrhea.
IPEX is an X-linked disorder resulting from mutations in FOXP3, which is a regulator of T-cell homeostasis, resulting in T cell overactivation. The disorder is characterized by multiple features, as in this patient. Diarrhea is the most common manifestation, and is usually severe and watery, but may have mucus or blood. Patients may be misdiagnosed initially as having inflammatory bowel disease due to some of the similar pathologic findings.
Other major clinical features are: failure to thrive (from the diarrhea and chronic illness), autoimmune manifestations including diabetes, hypothyroidism, hemolytic anemia and thrombocytopenia, recurrent infections, hepatosplenomegaly and lymphadenopathy. The degree of immune deficiency is variable, and is often worsened by the immunosuppressive therapy needed to treat the autoimmune manifestations.
Many of the common immunologic screens (such as serum immunoglobulins, complement levels and lymphocyte subsets) are often within normal limits. Bacterial infections are most common. IPEX is typically fatal in childhood, as it was for this patient, who died at age 12. Immunosuppressive therapies are typically used to control symptoms, but are not good long-term therapies for this disorder. Several patients have had curative bone marrow transplantation.
The main disorder in the differential for this patient is APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), which is an autosomal recessive disease resulting from mutations in the AIRE (autoimmune regulator) gene. APECED patients suffer from chronic mucocutaneous candidiasis starting at a young age, similar to our patient. Autoimmune manifestations follow, and are most commonly adrenal insufficiency and hypoparathyroidism. IPEX often differs from APECED in that there is profuse diarrhea, and an increased incidence of bacterial and other infections. No AIRE mutation was found for this patient.
Abnormal interferon-gamma receptor expression was raised because of the mycobacterial infection. However, the autoimmune features and Candida infections would be inconsistent. Hyper IgE (Job) syndrome has mucocutaneous candidiasis, bacterial infections and characteristic facial features. However, the autoimmune features and the profuse diarrhea would be inconsistent.
Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatology. 2003;15:430-435.
Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829-1836.
For more information:
- Alexandra F. Freeman, MD, is a Staff Clinician in the Laboratory of Clinical Infectious Diseases, NIAID, NIH and is an Assistant Professor of Pediatric Infectious Diseases at Georgetown University Hospital.
- Victoria Anderson, CDR, USPHS, MSN, CRNP, is a Nurse Practitioner in the Laboratory of Clinical Infectious Diseases, NIAID, NIH.
- We thank John Crawford and Mary King for clinical photographs, and Dr. Steven Holland for his editorial review.