A Patient with 22q11.2 Deletion Syndrome Presenting with Systemic Skin Rash and Dermatopathic Lymphadenitis of Unusual Histology

Background

Currently, chromosome 22q11.2 deletion syndrome (22q11.2 DS) includes DiGeorge syndrome (DGS), conotruncal anomaly face syndrome (CTAF), velocardiofacial syndrome, and Opitz G/BBB syndrome and Cayler cardiofacial syndrome when the chromosomal deletion is detected in patients with these syndromes [1]. Most of the patients with the first 2 syndromes and some of the patients with the latter 2 have the chromosomal deletion. The condition 22q11.2 DS is essentially a multi-system syndrome with a remarkable variability in the severity and extent of phenotypic expression in affected patients. We treated a patient who had 22q11.2 DS and manifested generalized skin rash and dermatopathic lymphadenitis (DL) with marked proliferation of spindle-shaped cells. There have been only a few reports on skin rash or erythroderma and lymph-adenitis in infants with DGS or 22q11.2 DS [2]. To the best of our knowledge, this is the first report to describe spindle cells proliferation in DL in 22q11.2 DS. We describe the unique microscopic changes and discuss the mechanism of this reaction in the lymph nodes.

Case Report

CLINICAL SUMMARY:

A healthy mother gave birth to a male infant with a birth weight 3458 g at 40 weeks of gestation by vaginal delivery. The Apgar scores were 8 and 8 at the 1st and 5th minutes after birth, respectively. A prenatal examination (or ultrasound screening) had indicated that he had interruption of aorta of Celoria Patton classification type B and ventricular septal defect (VSD). Immediately after birth, we found he had no uvula, but he did not have cleft lip or cleft palate. Clinically, no skeletal malformations were detected. On day of life (DOL) 8, bilateral pulmonary artery banding was performed. The thymus was not detected during the surgery or by ultrasonography or chest X-ray. On DOL31, fluorescence in situ hybridization method performed on the interphase nuclei of buccal smears detected the deletion of 22q11.2 (data not shown). On DOL33, he developed diffuse eczema throughout the body. Although infantile eczema, contact dermatitis, or viral infection was clinically suspected, laboratory tests could not determine the exact cause. A skin biopsy demonstrated vacuolar interface dermatitis with superficial perivascular infiltration of T-lymphocytes and macrophages (Figure 1A), and laboratory examination revealed eosinophilia (87%) and hypocalcemia (5.7 mg/dL). Finally, cutaneous inflammation was considered to have some relationship with the abnormal immune response in 22q11.2 DS. The infant was treated with corticosteroids, but the cutaneous lesions did not ameliorate. On DOL84, lymphocytopenia (lymphocyte count: 0.91×109/L) was observed. Low T cell functions were also confirmed by lymphocyte blast-transformation test induced by phytohemagglutinin and concanavalin A, with 7480 counts per minute (cpm) and 5750 cpm, respectively. Moreover, B cells proportionally decreased, whereas T cells increased, according to flow cytometric analysis. In the T cell population, most were CD8+, whereas CD4+ T cells were scarce. Most of the T cells were of activated memory type (HLA-DR+ and CD45RO+). In addition, CD45RA+ T cells, which showed recent thymic emigrants, were few. An oligoclonal proliferation of T cells was confirmed by T-lymphocyte receptor repertoire analysis. On DOL74, he suddenly went into shock because of arrhythmia due to hypocalcemia. Laboratory examinations revealed abnormal blood coagulation and elevated liver enzymes, while transthoracic echocardiography detected depressed myocardial contractility. Subsequently, treatment for disseminated intravascular coagulation and heart failure was started. On DOL95, he underwent aortic arch repair and intracardiac repair. Gradually, the cutaneous erosions worsened, and the lymph nodes in the axilla and inguinal regions became swollen. On DOL169, methicillin-resistant Staphylococcus aureus was found in the patient’s blood culture. On DOL210, the patient died due to sepsis caused by Pseudomonas aeruginosa infecting the skin. An autopsy was performed after obtaining informed consent.

PATHOLOGICAL FINDINGS:

Within 4 hours after death, an autopsy was performed. The systemic skin demonstrated widespread erythroderma with severe cutaneous erosions and hemorrhages (Figure 1B). Microscopically, the epidermis manifested erosive and necrotic change with marked bacterial infection, and the dermis exhibited severe lymphocyte infiltration. Many clefts were formed between the epidermis and the dermis, probably due to severe hemorrhages (Figure 1C).

There were numerous swollen lymph nodes, up to 2.2 cm in size, in the bilateral axillar and subclavicular areas, and around the bilateral iliac arteries (Figure 2). Cut surfaces of the lymph nodes bulged with homogenously brown discoloration and elastic soft consistency. Histology of the lymph nodes demonstrated a sparse distribution of atrophic germinal centers (Figure 3A). Several centroblasts and centrocytes were observed in the germinal centers, which were not surrounded by mantle zones; instead, they were surrounded by pale zones of proliferating spindle cells (Figure 3B, 3C). The spindle cells consisted of macrophages (positive for CD68 and CD163), Langerhans cells (positive for CD1a, Langerin, and S100p), and interdigitating dendritic cells (positive for S100p and negative for CD1a and Langerin) (Figure 4A–4I). In addition, some of the spindle cells co-expressed CD123 and CD56 by double immunostaining (Figure 4J–4L). Around the spindle-cell area, there were small lymphocytes aggregates, which were positive for CD3 and CD8 (Figure 4A, 4D); however, neither CD4+ lymphocytes (Figure 4C) nor PD1+ cells were found. The germinal centers did not contain CD4+ and PD1+ cells, either. Fontana-Masson staining revealed that the macrophages had numerous melanin particles (Figure 3D). Thus, these lymph nodes were diagnosed as DL.

Macroscopically, the thymic tissue was not detected in the cervix or in the mediastinum. The parathyroid glands were not found macroscopically or microscopically. The lungs (left 49.1 g, right 54.6 g) and liver (282.7 g) demonstrated a systemic inflammatory change. No other anomalies were discovered in the visceral organs.

Discussion

Children with DGS presenting with the clinical triad of immuno-deficiency, hyperparathyroidism, and congenital heart disease were originally described in the 1960s [3]. Nowadays, several seemingly unrelated conditions, including DGS, CTAF, and velocardiofacial syndrome, typically result from chromosome 22q11.2 deletion [3]. The main clinical features of 22q11.2 DS include congenital heart defects, palate deformities, facial dys-morphism, developmental delay, and various degrees of immunodeficiency and hypocalcemia. In the present case, aplasia of the thymus and parathyroid glands, anomaly in the heart and major blood vessels, and absence of uvula were manifested; there were no abnormalities other than developmental delay and facial dysmorphisms that we could not completely rule out as the patient was too young.

Immunodeficiency affects up to 75% of 22q11.2 DS cases, owing to the hypoplastic thymus or the functional abnormality, which leads to impaired T cell production. 22q11.2 DS has a wide range of T cell deficiency, from normal T cell numbers and function to the absence of T cells [4]. In fact, 1–2% of patients with complete lack of T cells have serious and potentially fatal conditions that are similar to severe combined immunodeficiency [4]. In some 22q11.2 DS cases, an oligoclonal proliferation of T cells has been observed [2]. The present case is consistent with these previous reports, considering that lymphocytopenia, low T cell function, and oligoclonal proliferation of T cells were found.

To date, only a few 22q11.2 DS cases have displayed severe eczema. Minakawa et al. presented a patient with 22q11.2 DS manifesting an itchy eruption, hyper-IgE level, and eosinophilia, mimicking atopic dermatitis [5]. The common association of primary immunodeficiency with allergies and autoimmune diseases raises the question of why immunodeficient patients can develop symptoms suggestive of immune-system hyperactivation. Recently, regulatory T cells (Tregs), which are a particular subset of T cells, have been implicated in the negative regulation of immune responses and prevention of immunological disorders [6]. Naturally, Tregs develop in the thymus, and FOXP3 genes are considered to play a key role in Treg differentiation. Mutation of the genes results in immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome [6], which is characterized by severe eczema, hyper-IgE level, and eosinophilia. Hence, impaired Treg function in primary immuno-deficiency can induce immune-system hyperactivation signs, such as severe eczema and eosinophilia, in 22q11.2 DS cases.

Pathological features of the lymph nodes in patients with 22q11.2 DS generally show a depletion of small lymphocytes in the paracortical regions [7], without significant abnormalities in germinal center formation [7]. There have been only a few reports on skin rash or erythroderma and lymphadenitis in infants with DGS or 22q11.2 DS. Markert et al. reported that the lymph nodes of these patients revealed atrophic germinal centers surrounded by CD8+ T cells and histiocytes [2]; they did not describe spindle-cell proliferation in the lymph nodes. To the best of our knowledge, this is the first report concerning spindle cells proliferation in DL in 22q11.2 DS. It is also interesting that DL in most patients (probably without 22q11.2 DS) does not show spindle-cell proliferation, while a nodular expansion of the paracortex by pale-staining macrophages with melanin pigments could be seen [7].

We believed that the marked proliferation of spindle-cell in the lymph nodes in the present patient represented an extraordinary histology of DL in 22q11.2 DS. The spindle cells mainly consisted of macrophages, Langerhans cells, and interdigitating dendritic cells. Interestingly, some of the spindle cells expressed both CD123 and CD56. Therefore, we supposed some of them had the immunohistochemical phenotype of plasmacytoid dendritic cells (PDCs). However, we could not determine the cell lineage of the CD123 and CD56 double-positive cells, because in addition to PDCs, CD123 is expressed on other several cells such as myeloid lineage cells and activated T cells, among others. Further experiments are needed to confirm the cell lineage. In the present case, thymic agenesis and T cell immunodeficiency led to an abnormal immune status. Given this unusual immune condition in 22q11.2 DS, lymph nodes in the systemic skin inflammation may show an extraordinary histology of increased proliferation of spindle cells around the atrophic germinal center.

Conclusions

DL in the present 22q11.2 DS patient demonstrated unusual histological features. The marked proliferation of spindle-shaped cells is a unique finding that has not been reported before in the English literature. Hence, accumulation of cases and further investigations are necessary to confirm the precise pathogenesis of these characteristic changes.