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Consanguinity in marriages can lead to many genetic abnormalities in the offsprings. The children are affected in varying degrees of severity. Autoimmune lymphoproliferative syndrome is an example of a genetic abnormality wherein there is an absence of apoptosis of lymphoproliferative cells, hence leading to enlargement of lymph nodes and spleen and associated autoimmune abnormalities. Autoimmune lymphoproliferative syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programed cell death. In the immune system, antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minimizing reactions against self-antigens. In autoimmune lymphoproliferative syndrome, defective lymphocyte apoptosis manifests as chronic, nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4–CD8–T cells; and the development of autoimmune disease. Most cases of autoimmune lymphoproliferative syndrome involve heterozygous mutations in the lymphocyte surface protein Fas (CD95, Apo1) that impair a major apoptotic pathway.
Here, we report a case of a 10 year old child with recurrent multiple swellings in the head and neck region.
Autoimmune lymphoproliferative syndrome, apoptosis, generalized lymphadenopathy
Lymphadenopathy in children with no known infectious or malignant cause constitutes a challenging diagnostic dilemma. A recently described entity that deï¬nes some children with previously unexplained lymphadenopathy is the autoimmune lymphoproliferative syndrome (ALPS). The clinical antecedents to ALPS entail various syndromes of familial chronic nonmalignant lymphadenopathy and splenomegaly, including pseudomononucleosis, pseudolymphoma, and the Canale-Smith syndrome.1
Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of disrupted lymphocyte homeostasis characterized by chronic splenomegaly and lymphadenopathy of early onset, hypergammaglobulinemia (Ig G and Ig A), autoimmune phenomena, and expanded populations of T cells, called double negative T-cells (DN) T cells.2
Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS).
It is a disorder characterized by generalized, nonmalignant lymphadenopathy,hypergammaglobulinemia, lymphocytosis, splenomegaly, and autoimmune phenomena. A distinct feature of ALPS and an early clue to its nature, is the occurrence of markedly increased numbers and percentage of T cell receptor (TCR)-ab CD42 CD82, double negative (DN) T cells in the circulation and lymphoid tissues. 3
We report the case of a patient who had come to our department with multiple swellings in the head and neck region.
A 10 year old male patient had come to the Department of Oral medicine and Radiology with the chief complaint of pain in the lower right back region of the jaw since a day. The patient had pain and swelling in the lower right back teeth region since a day which was moderate to severe, intermittent, aggravates on having food and relieves on its own.
His past medical history revealed bilateral neck region swellings at the age of 1 and a half yrs for which he was treated with oral medications. History of developing a swelling in the axilla following BCG vaccination and was diagnosed as BCG adenitis and was treated for the same. At the age of 6 yrs he developed bilateral neck swellings for which he was referred to a pediatrician in 2009. Hematology report revealed normochromic normocytic anemia with neutrophilic lymphocytosis, FNAC of the cervical lymph node suggested necrotizing granulomatous lymphadenitis and was treated with oral antibiotics.
At seven and a half yrs of age patient developed bilateral cervical lymphadenitis with abscess formation which lasted for 8 to 10 months which healed with scarring. Patient gives a history of a severe form of chicken pox , scars have remained all over the body. ESR was elevated at 110. Ultrasound of abdomen revealed mildly enlarged inguinal lymph nodes with mild hepatomegaly. The patient’s axillary and inguinal lymph nodes biopsy specimen was given for histopathology and immunohistochemistry analysis. A report of reactive lymphadenitis was obtained. Skin biopsy of rashes on lower limbs revealed lymphocyte perivasculitis. Patient also gave a history of joint pain of his lower limbs. His HIV status was negative and his random blood sugar was within normal limits.Ultrasound of abdomen and neck done recently revealed multiple mesenteric and non necrotic cervical lymphadenopathy.
On general physical examination, patient appeared malnourished, lethargic with protruded abdomen and generalized healed scars of chicken pox were also observed(Fig. 1 and 2) and scar in left inguinal region.On extraoral examination there was a well defined swelling on face on the right side extending superiorly from the mid third of the face, inferiorly to the submandibular region, mesially from the corner of the mouth and distally below the ear lobule (Fig.3). On palpation, swelling was soft to firm in consistency, tender on palpation with rise in surface temperature. On inspection of the neck, there was a diffuse swelling of the submental and submandibular lymph nodes , raising the ear lobules. On the left side of the neck lymph enlarged node seen one below the ear lobule and another on the lateral aspect of neck, associated with scar of previous biopsy (Fig. 4). On palpation, bilaterally submandibular and submental lymph nodes were palpable measuring approximately 3x3cm , firm to hard in consistency, fixed, tender on palpation and all cervical lymph nodes were palpable and tender, variable in size.
On intraoral examination, on inspection there was vestibular erythema and obliteration with swelling in relation to 55 on the buccal vestibule and on palpation swelling was firm in consistency, with vestibular tenderness was elicited. On hard tissue examination, presence of mixed dentition and deep dental caries with tenderness on percussion positive with 55. The diagnosis of acute exacerbation of chronic periapical abscess with 55 with buccal and submandibular space infection was considered.
With the history of consanguineous marriage of his parents, his younger sibling having similar and milder symptoms with BCG adenitis, generalized unexplained lymphadenopathy, severe form of chickenpox, joint pain of lower limbs and vasculitis of skin lesions and based on the histopathology and immunohistochemistry reports of the lymph nodes a diagnosis of autoimmune lymphoproliferative disease was given.
The treatment given to the patient was syrup naprosyn 125mg for 5 months 6ml b.d. The treatment planned for him was
- Fas mutation for confirmation
- Tab Wysolone (1mg/kg/day) with inj Methotrexate (15mg/m2 ) as a steroid sparing agent
- Tab Shelcal/calcitriol sachet ½ sachet /month (50 mg/kg/day).
The patient after 1 month follow up post treatment, there is no reduction in the size of lymph nodes. His blood reports revealed marked increase in the level of immunoglobulins. Presently the patient complains of inguinal pain and swelling since 6 months , which has not regressed even after treatment and he is unable to walk due to the pain.
But the patient, on consequent follow up visits, General appearance of the patient has improved. (Fig. 5,). He showed decrease in the size of the lymph nodes except for residual scars of the fibrosed lymph nodes in the right lateral cervical regions. (Fig.6, 7, 8)
The autoimmune lymphoproliferative syndrome (ALPS) is a rare disease. ALPS is a rare inherited condition that affects both sexes. ALPS generally does not lead to death and most individuals with ALPS are able to live normal lives. ALPS is a disorder associated with abnormal lymphocyte apoptosis, lymphoproliferation, and autoimmunity. Lympho proliferation in ALPS patients is generally benign, but they are at increased risk for the development of Hodgkin’s and non-Hodgkin’s lymphoma. It is characterized by massive lympho adenopathy, splenomegaly, autoimmunity including episodes of immune hemolytic anemia, thrombocytopenia,and neutropenia. ALPS patients have lymphocytosis and a number of lymphocyte abnormalities, including the marked expansion of T lymphocytes that express alpha/beta T-cell receptors, but neither CD4 nor CD8 surface markers (TCR alpha/beta+; CD4–; CD8– cells).4
ALPS is subdivided into: 1) Type Ia, ALPS with mutant Fas; 2) Type Ib, lymphadenopathy and mutation in the ligand for Fas in one patient with systemic lupus erythematosus; 3) Type II, ALPS with mutant caspase 10; and 4) Type III, ALPS as yet without any defined genetic cause. 5
In type 0 disease, homozygous Fasmutations usually cause a complete deficiency of the Fas protein and a severe form of the disease.In ALPS type I, heterozygousFasmutations (ALPS type Ia)or, more rarely, heterozygous mutations in the gene for Fas ligand (ALPS type Ib)are usually associated with a partial defect in apoptosis mediated by Fas and its ligand. ALPS type II, which is characterized by resistance to Fas-mediated apoptosis despite the presence of normal Fas ligand and Fas, with caspase 10 mutations. In ALPS type III, Fas-mediated apoptosis is also normal,and the genetic defect is unclear. Patients with ALPS type III may not have all four classic features of the syndrome — lymphoproliferation, excessive numbers of double-negative T cells, hypergammaglobulinemia, and autoimmune manifestations. Many cases of ALPS type III are sporadic, precluding the use of a genetic approach to identify the molecular defect 6
A study done by Michael Sneller et al 7 to study the lymphocyte apoptosis, revealed that ALPS was identified in 9 unrelated individuals with moderate to massive spleenomegaly, lymphadenopathy, hypergammaglobulinemia and autoimmunity, B cell lymphocytosis and an increase in the population of D4/CD8 T cells. All these findings coorelated to our case in which there were similar findings.
Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death. as (also called apo-1 and cd95) is a cell-surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily (Fas is the sixth member, TNFRSF6). Fas initiates a cascade of events within the cell that culminates in the death of the cell (apoptosis). This process involves the formation of the death-inducing signaling complex, consisting mainly of the Fas associated death domain and the caspase 8 and caspase 10 proteins. The constellation of lymphadenopathy, splenomegaly, and autoimmune cytopenia, however, was described by Canale and Smith in 1967, Weisdorf and Krivit and others noted that similar patients had decreased proportions or function of lymphocyte subsets.8 This heterozygous dominant mutations of Fas were found in children with the autoimmune lymphoproliferative syndrome (ALPS),which is also known as the Canale–Smith syndrome. 4
ALPS manifestations usually appear in the first 5 years of life (median onset at 3.5 years). The most frequent presentation of ALPS is a benign lymphoproliferation limited to lymphoid organs.9 Enlargement of spleen and lymph nodes is the most prominent feature of the lymphoproliferation in nearly all ALPS patients.
Autoimmunity is the second most salient feature of ALPS. Autoimmune cytopenias account for more than 80% of the autoimmune manifestations and are, essentially, autoimmune hemolytic anemia, thrombocytopenia and, sometimes, neutropenia.9
Fas and FasL are members of two superfamilies of complementary receptors and ligands that are important in immune regulation. These membrane-spanning receptors have 20%-25% amino acid identity and contain variable numbers of extra- cellular cysteine-rich domains (CRDs) regions approximately 40 amino acids in length with six cysteine residues in conserved positions. There are four CRDs in the p55 TNFR and three in the Fas protein. These two receptors share a 70 amino acid intracellular “death domain” that transduces signals for cell death.10
The diagnosis and management of autoimmune lymphoproliferative syndrome (ALPS) remains a challenge to the oral diagnostician. Knowledge of immunological aspects of oral diseases is a new frontier for any oral healthcare professional. These patients require prompt treatment and long term follow-up, by multiple specialists that are familiar with ALPS. It is imperative that all cases with oral manifestations are reported.
The diagnosis of Autoimmune lymphoproliferative disorder should be kept in mind as one of the differential diagnosis in a patient with generalized lymphadenopathy with the history of consanguinous marriage in the family. This case report is one more effort in this direction.
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