A well-demarcated punched-out deep ulcer on the whole tip of the tongue of patient 1.
A well-demarcated punched-out ulcer on the vulvar area of patient 1.
A well-demarcated deep punched-out ulcer on the perineum of patient 5.
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Kwong PC, O'Marcaigh AS, Howard R, Cowan MJ, Frieden IJ. Oral and Genital Ulceration: A Unique Presentation of Immunodeficiency in Athabascan-Speaking American Indian Children With Severe Combined Immunodeficiency. Arch Dermatol. 1999;135(8):927–931. doi:10.1001/archderm.135.8.927
Oral and genital ulcerations have been previously reported in 3 Navajo children diagnosed with severe combined immunodeficiency disease with T- and B-cell lymphopenia (T−B−–SCID).
To evaluate the occurrence of oral and genital ulcerations in 12 Athabascan-speaking American Indians with a diagnosis of T−B−–SCID (SCIDA group) and to compare their occurrence in non–Athabascan-speaking children with SCID (control group). We also observed the course of these ulcerations in response to bone marrow transplantation (BMT).
Retrospective survey of the medical records of patients with SCID admitted from December 1, 1986, through July 31, 1995.
Pediatric Bone Marrow Transplantation Division at a university hospital.
Twelve children in the SCIDA group and 21 in the control group. All patients had virtual absence of T- and B-cell numbers and function at time of diagnosis.
Oral and/or genital ulcers developed as a presenting feature of the SCIDA group. These ulcerations were not observed in the 21 controls. All patients underwent BMT. Of the 10 patients with oral and/or genital ulcerations, 3 had poor T-cell reconstitution after BMT, with recurrences of ulcers requiring additional BMTs.
Oral and/or genital ulcerations are common in Athabascan-speaking American Indian children with T−B−–SCID but are not seen in non–Athabascan-speaking children with SCID. Thus, oral and/or genital ulceration appears to be an important, distinctive finding, and often a presenting feature of immunodeficiency in Athabascan-speaking American Indian children with SCID. Bone marrow transplantation with successful T-cell engraftment appears to be curative in the resolution of the ulcers, with recurrences only in patients who had poor T-cell reconstitution.
SEVERE COMBINED immunodeficiency disease (SCID) encompasses a group of heterogeneous genetic disorders that are characterized by a profound deficiency in humoral and cell-mediated immunity.1,2 The mode of inheritance can be autosomal recessive or X-linked.2 These disorders are rare, with an estimated incidence in the general population of 2 per 1 million live births in the autosomal recessive form and 1 per 1 million live births in the X-linked form.2
The incidence of T- and B-cell SCID (T−B−–SCID) is increased in Athabascan-speaking American Indians,3 a population that includes the Navajo, Apache, and Dogrib tribes.4 The Navajo and Apache live on geographically distinct reservations in Arizona and New Mexico, whereas the Dogrib Indians are part of the Dene Nation in the Canadian Northwest Territories. Autosomal recessive transmission has been demonstrated as the mode of inheritance in the Athabascan type of SCID (SCIDA).3 All affected individuals have profound T and B lymphopenia, with very low or absent lymphocyte proliferation in response to mitogens and alloantigens. No other hematopoietic cell lineages are affected.4
The clinical manifestations of SCID can be quite diverse and nonspecific, with most infants presenting within the first 2 months of life with life-threatening infections, failure to thrive, and diarrhea.1 The cutaneous manifestations reported in patients with SCID are likewise varied, ranging from recalcitrant eczematous lesions to erythroderma.5 The diagnosis of SCID can be delayed because of the variable presentations of the disorder. Prompt diagnosis of SCID is crucial because, left untreated, the disease is fatal, usually within the first 6 months of life. At present, bone marrow transplantation (BMT) is the only available curative treatment for SCID.6
In 1986, Rotbart et al7 described 3 Navajo children with SCID who presented with oral and genital ulcerations. In their report, these ulcerations were called noma because of their similarity to the oral and genital ulcerations previously described mainly in malnourished children in developing countries.8,9 In our report, we study the occurrence of oral and/or genital ulcerations in 12 Athabascan-speaking American Indians with SCIDA, describe the course of these ulcerations after BMT, and compare the occurrence of such ulcerations in a non-SCIDA control group.
We reviewed the medical records of 12 Athabascan-speaking American Indian children with a diagnosis of SCIDA, all of whom were referred for a BMT to the University of California, San Francisco, Pediatric Bone Marrow Transplantation Division from December 1, 1986, through July 31, 1995. Relevant clinical summaries for all 12 patients are listed in Table 1.
The medical records of 21 non–Athabascan-speaking patients with SCID who were referred to the division during the same period and who had undergone the same routine assessment and preparation before BMT were also reviewed; these patients served as a control group.
Those patients presenting with oral and genital ulcers underwent evaluations using results of potassium hydroxide smears, Tzanck tests, and cultures for bacteria, acid-fast bacilli, fungus, cytomegalovirus, and herpes simplex virus.
A diagnosis of oral and genital ulceration related to SCIDA was made on the basis of the clinical description of oral or genital ulcers, which were persistent and rapidly progressive during a short time with no evidence of a specific microbiological agent causing the ulcer.
All of the patients enrolled in the program underwent similar conditioning protocols before their BMT. Successful reconstitution of T cells was an absolute T-cell count of at least 0.5×109/L and of donor origin with lymphocyte proliferative responses to alloantigens (mixed lymphocyte culture) and phytohemagglutinin within or near normal. Successful B-cell reconstitution was defined as an absolute B-cell count of greater than or equal to 0.2×109/L, normal IgG and IgM levels while not receiving intravenous immunoglobulin therapy, and documented specific antibody responses to protein and/or polysaccharide antigens or natural viral infections.6
Among the 12 patients with SCIDA, 10 were of Navajo Indian origin and 2 were of Dogrib origin. Oral and/or genital ulcers as a presenting feature had developed in 10 of the 12 patients (Table 1). At diagnosis, all of the children had virtual absence of T- and B-cell numbers and function (data not shown).
Representative typical oral and genital ulcers are shown in Figure 1, Figure 2, and Figure 3. These ulcers were sharply marginated with nonerythematous margins and clean bases without drainage. They were deep but did not invade contiguous structures such as muscles and bones. Ulcers developed before BMT in 7 of the 10 patients, and after BMT in the remaining 3. In the 10 patients presenting with ulcers, cultures for herpes simplex virus, cytomegalovirus, acid-fast bacilli, and fungus yielded negative findings. Some yielded mixed flora. Only 1 biopsy was performed on a genital ulcer, and the speciman showed ulceration with mixed dermal inflammation using negative special stains for microorganisms. There was no evidence of a thrombotic process as the cause for the ulceration.
All of the patients presenting with ulcers were eventually treated with broad-spectrum intravenous antibiotics, topical nystatin, and intravenous acyclovir. In addition, all the patients underwent a thorough nutritional assessment, and if their nutritional status was deemed suboptimal, they received supplementation with total parenteral nutrition. Some of the ulcers progressed rapidly before this treatment regimen but stabilized after treatment. Ultimately, the ulcers of all patients healed after their BMT. However, of the 10 patients with healed ulcers, 3 patients had recurrences of their ulcers (Table 2). These same patients also failed to achieve functional T-cell reconstitution and subsequently needed additional BMTs. Bone marrow transplantation therefore appeared to be curative for these ulcers, with successful T-cell engraftment being more important than successful B-cell engraftment (Table 2). There was no major sequela of facial or genital mutilation, salivary leaks, disfigurement, maldevelopment, or trismus in these patients.
As a control group, we reviewed the records of 21 non–Athabascan-speaking children with SCID who were referred during the same period. The absolute lymphocyte counts, absolute T- and B-cell counts, and mixed lymphocyte cultures of the SCIDA group were compared with those of the control group. As illustrated in Table 3, the immune status of the SCIDA group appeared to be significantly lower than that seen in the control group at the time of diagnosis. Furthermore, none of the control group presented with oral or genital ulcers.
Severe combined immunodeficiency with T- and B-cell lymphopenia is a relatively common inherited disorder in Athabascan-speaking American Indians,3 with an estimated incidence of 1 in 2000 in the Navajo population.3 Approximately 2% of the Navajo population are thought to carry the defective gene.3 The mode of inheritance is autosomal recessive, with multiple affected siblings and unaffected parents.3,4
The Athabascan-speaking American Indians found to have an increased incidence of TB-SCID belong to the Navajo, Apache, and Dogrib tribes. These tribes are not directly related to each other, but it is believed that they share the same ancestors. Historically, the Athabascan-speaking people were hunter-gatherer groups who originated from the Northwest Territories. Around 700 AD, the Na-Dene subdivision of the Athabascan-speaking group began migrating into the southwestern United States and toward the end of the 17th century separated into 2 tribes, now known as the Navajo and Apache. The Dogrib tribe is a small Athabascan-speaking Indian tribe that still lives in the Northwest Territories. Recently, the SCIDA gene was linked to markers on chromosome 10p.4
Rotbart et al7 described oral and genital ulcerations in 3 Navajo children with a diagnosis of SCID, referring to them as noma. Noma is a term that has been used for rapidly progressive ulceration, mainly around the oral cavity, in children from developing countries.8,9 The causes in developing countries are diverse, including chronic malnutrition, infection (especially pseudomonas), and immunodeficiencies.8,9 The cases described by Rotbart et al7 were aggressive and extensive and progressed despite antibiotic treatments and attempted correction of immunodeficiencies using BMT. Although in these cases, as well as others described by Jones et al,10 the skin lesions were severe enough to warrant the descriptive term noma, none of our cases were this severe. They were typically punched out and deep, expanding in a circumferential fashion but without extension to contiguous deep structures. The ulcers did not result in functional sequelae and did not leave conspicuous scars. These findings, undoubtedly mitigated by the correction of immunodeficiency with successful BMT, were not as severe or destructive as those of noma. We believe these ulcerations are a specific feature of SCIDA and, because of the clinical differences, should not be called noma.
Ulcers developed in most of our patients before BMT; however, in 3 patients, the ulcers occurred after BMT. Although mucosal ulcers can develop secondary to many conditioning regimens for BMT, several features argue against this as a cause. First, the clinical appearance of these ulcers was not compatible with the diffuse mucositis seen in patients after BMT, with more focal and deeper ulcerations noted. Second, genital ulcers also developed in several patients, which is uncommon after BMT. Third, the conditioning regimen involved the use of cyclophosphamide (Cytoxan), 50 mg/kg, which only rarely causes mucositis. Fourth, the development of mucositis after BMT is usually immediate, and the development of these ulcers occurred at least 1 month after BMT. Mucosal ulcerations can develop with graft-vs-host disease; however, none of these patients had evidence of graft-vs-host disease in other organ systems. Indeed, all 3 showed lack of immune reconstitution and required further transplantations to restore immunity. Thus, the development of oral and/or genital ulcers in these 3 patients after BMT was still most likely due to their genetic immunodeficiency.
To our knowledge, oral and genital ulcerations have not been observed in patients of non–American Indian origin with SCID. Our control group had undergone the same conditioning regimen as our SCIDA group, but no ulcers developed before or after BMT. Thus, oral and genital ulcerations appear to be an important, distinctive marker and often a presenting feature of T-B-–SCID in these American Indian populations. A mother of 1 child with SCIDA reported that "she had had 4 children die of the same condition, with the skin lesions being, for her, the most characteristic feature."10
The management of ulcerations in our study included broad-spectrum antibiotic coverage, optimal nutritional support, and local wound care. This mode of treatment appeared to stabilize the progression of the ulcers. This may also explain the less extensive nature of the ulcers observed in these patients. There were no major sequelae of mutilation or disfigurement reported. Bone marrow transplantation with successful T-cell engraftment regardless of B-cell recovery appeared to be curative in the resolution of the ulcers, with recurrences observed only in patients who had inadequate T-cell reconstitution. Thus, our results suggest that correcting the underlying predisposing factor(s) may actually be the most effective form of treatment.
The pathogenesis of ulcerations in patients with SCIDA may be multifactorial. One of the predisposing factors may be their significantly lower immunity compared with their non–Athabascan-speaking counterparts. However, it should be emphasized that the pathogenesis of these ulcers is not based solely on immunodeficiency. Low cell counts are not necessarily absolute predictors for the development of these ulcers. Other factors, such as genetics, may also play a role. It will be interesting to determine if there is a link between the specific genetic mutation in SCIDA and the tendency for these ulcers to develop, in addition to their immunodeficiency.
Persistent oral and/or genital ulcers in young children are rare. Infectious causes should be sought out, but, if not proven, other causes, such as pyoderma gangrenosum, erythema multiforme, Behçet syndrome, acatalasemia, and autoimmune bullous disorders, should be considered. As our report notes, underlying systemic disorders, particularly immunodeficiencies, can also cause oral and/or genital ulcerations. Such a presentation in an infant of American Indian descent, in particular an Athabascan speaker, is a sign of congenital immunodeficiency until proven otherwise. Since SCID is curable with BMT, early diagnosis can lead to prompt intervention and prevention of complications.
Reprints: Pearl Kwong, MD, PhD, Department of Dermatology, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.
Accepted for publication February 24, 1999.
This study was supported in part by grants AI28339 from the National Institutes of Health, Bethesda, Md, and 95-0954 from the March of Dimes, New York, NY, and by Women's Dermatologic Society Mentorship Grant, Schaumburg, Ill.
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