The unusual association of three autoimmune diseases in a patient with Noonan syndrome
Article Outline
Abstract
Abstract
We report on a 26-year-old female affected by Noonan syndrome (NS), a congenital disorder characterized by various phenotypic features and congenital anomalies) associated with a variety of autoimmune diseases, including systemic lupus erythematosus, celiac disease, and Hashimoto thyroiditis. Autoimmunity is seldom described in NS and the association between this congenital disease and three autoimmune disorders has not been previously reported. Should the occurrence of autoimmune disorders in NS be confirmed, a relevant clinical and laboratory evaluation of NS patients should be performed in order to clarify whether the immune system involvement represents only an occasional event or is a feature of the disease.
Keywords: Adolescent autoimmunity, Noonan syndrome, Systemic lupus erythematosus, Celiac disease, Hashimoto thyroiditis
Noonan syndrome (NS) is a rare congenital disorder characterized by various phenotypic features and congenital anomalies including short stature, congenital cardiac defects, dysmorphic facies, webbed neck, skeletal and genital anomalies and mild mental retardation 1, 2. Approximately half of all cases are sporadic, but autosomal dominant inheritance with variable expression is well-established [3]. The diagnosis of this syndrome still rests on its clinical features.
NS has been also associated with coagulation defects, neurological involvement, myelo- or lympho-proliferative disorders and lymphatic abnormalities. Autoimmune diseases have rarely been described in NS 4, 5, 6, 7.
We report the case of a young female with Noonan syndrome and a variety of autoimmune disorders, such as systemic lupus erythematosus (SLE), celiac disease (CD) and Hashimoto thyroiditis (HT).
Case report
In July 1998, a 26-year-old Caucasian female with Noonan syndrome was admitted for a clinical revaluation of the disease. Her family history was unremarkable.
At 30 days of age, an echocardiogram showed pulmonary stenosis, atrial septal defect, mitral valve prolapse and moderate aortic, mitral, and tricuspid valvular insufficiency. During her infancy, the patient showed abnormally retarded development, multiple morphologic abnormalities, and mental retardation. A chromosomal analysis demonstrated a normal 46 XX karyotype and the diagnosis of Noonan syndrome was made on the basis of clinical findings (Table 1).
Table 1. Clinical Features of Noonan Syndrome in Our Patient
| Morphological Abnormalities |
| Physical hypoevolutism |
| Short stature |
| Chest deformity |
| Webbed neck |
| Dysmorphic facies |
| Wide-set eyes |
| Antimongoloid slant |
| Flat forehead |
| Curly hair |
| Congenital heart defects |
| Hepato-splenomegaly |
| Neuropsychiatric Disorders |
| Mental retardation |
| Epilepsy |
At age 18 years, because of the onset of generalized convulsions, she underwent electroencephalography and computed tomography of the brain. No abnormalities were found; nevertheless, seizures repeatedly occurred. Her epilepsy was controlled with appropriate therapy (carbamazepine 400 mg/day). At the same time, she developed HT diagnosed according to the usual criteria (typical findings on thyroid gland ultrasound imaging, high levels of antithyroglobulin and antimicrosomal antibodies, and increased serum thyroid-stimulating hormone levels >5 mIU/mL, with subnormal FT4 levels). She showed overt hypothyroidism and required L-thyroxine treatment (75 mcg/day).
One year later, she complained of abdominal pain and diarrhea. CD was suspected. IgG and IgA antigliadin and IgG antiendomysial antibodies were positive; small-intestinal biopsy findings were consistent with gluten enteropathy. After a gluten-free diet, the diarrhea subsided and the patient showed weight gain.
In April 1998, the patient had menorrhagia, fever, weakness, and diffuse arthralgias. Laboratory tests showed an erythrocyte sedimentation rate (ESR) of 76 mm/h; hemoglobin, 5.7 g/dL; platelet count, 17,000/mm3; red blood cells, 2,020,000/mm3; white blood cells, 11,100/mm3 (84% neutrophils and 5% lymphocytes); positive antinuclear antibodies (ANA) at a titer of 1:640; kaolin clotting time ratio 1.47; and Coombs test (anticomplement type), positive. On the basis of these data, thrombotic thrombocytopenic purpura (TTP) (Moschcowitz syndrome) was erroneously diagnosed. Corticosteroid therapy was administered (prednisone 12.5 mg/day) in association with platelet antiaggregant therapy (dipyridamole 225 mg/day). The patient underwent daily plasma-exchange courses. Fever subsided, and platelet count and hemoglobin levels increased (205,000/mm3 and 9.1 g/dL, respectively).
In July 1998, arthralgias and fever recurred, and the platelet count dropped abruptly (35,000/mm3). For this reason the patient was admitted to our department. She was both short and small for her age, had dysmorphic facies with wide-set eyes and an antimongoloid slant. Her neck was short and webbed, and she had other marked features, including a flat forehead and pectus carinatum. Examination of the abdomen revealed hepatosplenomegaly. Laboratory findings demonstrated the positivity of ANA at a titer of 1:640 (homogeneous pattern), anti–double-stranded DNA (anti-dsDNA) and anti-Sm antibodies, lupus anticoagulant (LAC) test, and IgG and IgM anticardiolipin antibodies (aCL). C3 and C4 levels were decreased. ESR was increased (64 mm/h). Anemia (Hb 9.5 g/dL) and lymphocytopenia (550 cells/mm3) were also found. A rheumatoid arthritis test was negative. Our investigations did not support the diagnosis of TTP.
Within a few days her symptoms worsened, as she developed progressive chest constriction and dyspnea. An echocardiography revealed the presence of pericardial effusion. On the basis of clinical features (arthralgias, pericardial effusion, and seizures) and laboratory data (thrombocytopenia, anemia, lymphocytopenia, high titer of ANA, positivity of LAC, and high IgG and IgM aCL levels), the patient fulfilled the American College of Rheumatology (ACR) criteria for SLE classification. Corticosteroid therapy was increased to 37.5 mg/day (i.e., 1 mg/kg/day). Her clinical conditions improved and the pericardial effusion disappeared within 1 month.
In August 1998, visually evoked potentials showed bilateral abnormalities. Electroencephalography revealed abnormal, repetitive, rhythmic activity in the right occipital area, consistent with epilepsy. In addition, magnetic resonance imaging of the brain showed cortical and subcortical atrophy without focal lesions.
In September 1998, carbamazepine treatment was suspended because it could have increased the positivity of antinuclear antibodies, and instead a valproic acid treatment (600 mg/day) was started.
After 2 months of follow-up, laboratory tests showed the presence of ANA (1:1280, periferic pattern), anti-dsDNA (1:40) and IgG and IgM aCL antibodies (13.7 U/mL and 57.2 U/mL respectively; normal range 0–10 U/mL). Prednisone treatment was continued with progressive improvement of arthralgias, regression of fever and recovery of thrombocytopenia (platelets 173,000/mm3).
In September 1999, cyclosporin A treatment (75 mg/day) was started and prednisone therapy was progressively reduced to 12.5 mg/day. Currently (October 2001), the patient is without symptoms.
Discussion
The unusual association of multiple autoimmune diseases, such as SLE, CD, and HT with a rare congenital syndrome prompted us to describe this unique clinical case (Table 2).
Table 2. Laboratory and Clinical Features of Autoimmune Diseases in Our Patient
| Systemic Lupus Erythematosus | |
| ESR | 64 mm/h |
| Hb | 9.5 g/dL |
| Lymphocytes | 550/mm3 |
| Platelet count | 35.000/mm3 |
| Coombs test | Positive |
| ANA | Positive (1:640) |
| Anti-dsDNA | Positive (1:80) |
| Anti-Sm | Positive |
| LAC | Positive |
| IgG and IgM aCL | Positive (high levels) |
| C3, C4 | ↓ |
| Seizures | |
| Arthralgias | |
| Serositis | |
| Hashimoto Thyroiditis | |
| Thyroid-stimulating hormone | ↑ |
| FT4 | ↓ |
| Antimicrosomal antibodies | Positive |
| Antithyroglobulin antibodies | Positive |
| Celiac Disease | |
| IgG and IgA antigliadin antibodies | Positive |
| IgG anti-endomysial antibodies | Positive |
| Small-intestinal biopsy | Positive for celiac disease |
| Malabsorption | |
Some cases of NS have been associated with a number of neurologic manifestations, such as mental retardation, epilepsy, cortical dysplasia, and hydrocephalus [8]. Our patient presented with mental retardation and had suffered from seizures since age 18 years. It is very difficult to establish if epilepsy was a “prodromal” neurological symptom of SLE or if it was a NS manifestation. In SLE patients seizures are frequent and can be associated with aCL. In our screening, when the patient was referred to our department, the determination of aCL was positive. Robertson et al. [9] described a child affected by NS associated with cerebral infarction and seizures. Detailed laboratory tests failed to demonstrate any tendency toward thrombosis in this patient. Although LAC was negative, it is well-known that a negative test does not exclude per se the presence of aCL, which we did not investigate.
When this patient was aged 18 years, the diagnosis of HT was formulated according to the usual criteria. Autoimmune thyroiditis associated with NS is not frequent 5, 6. Conversely, autoimmune thyroid diseases are often found in SLE patients [10].
The association of NS with CD has not been previously described. Involvement of the gastrointestinal tract in SLE is well-documented, but the coexistence of SLE and CD sprue has rarely been reported [11]. In our patient, IgG and IgA antigliadin and IgG antiendomysial antibodies were positive, and small-intestinal biopsy findings confirmed the diagnosis of gluten enteropathy.
At age 26 years, the patient was diagnosed with TTP. However, at that time the patient fulfilled the ACR criteria for SLE classification (seizures, arthralgias, pancytopenia, positivity of antinuclear antibodies, and LAC). The differential diagnosis between SLE and TTP may often be difficult even when distinctive clinical and laboratory features are present. Few cases have been reported about the association between TTP and SLE and the link between the two diseases is still unclear [12]. However, a correct diagnosis is problematic when TTP and SLE appear simultaneously or when TTP complicates the course of SLE. In some patients affected by antiphospholipid antibody syndrome, TTP may be erroneously diagnosed. Thrombocytopenia and hemolytic anemia are immune mediated in SLE, while in TTP they are due to a microangiopathic process.
In our patient, ANA, anti-dsDNA, LAC, aCL, and the Coombs test were positive. These tests together with all of the above-mentioned clinical criteria, confirmed the diagnosis of SLE.
Platelet function and coagulation-factor defects, such as von Willebrand disease and factor II and XI deficiency, have been reported in NS 13, 14. Persistent thrombocytopenia was described in one of the early patients observed by Noonan [15] and other cases of low platelet count have been reported in this syndrome 14, 16. Infectious and immune causes for congenital thrombocytopenia have been excluded [16]. The test for antiplatelet antibodies has seldom been performed, and no increase of either IgG or IgM was found except in one case [4]. In some patients, bone marrow aspiration showed decreased megakaryocytes 14, 16. In the case we report, thrombocytopenia represented a manifestation of SLE.
Many cardiovascular disorders have been described in NS: congenital heart disease, such as pulmonary valvular stenosis and atrial sectal defect are present in half of the patients. Hypertrophic cardiomyopathy has also been reported [3]. In our patient, pulmonary stenosis, mitral prolapse and moderate aortic, and mitral and tricuspid valvular insufficiency were documented.
We do not know whether there is an etiologic relationship between autoimmune disorders and NS. It can be hypothesized that the susceptibility to autoimmunity in NS patients represents another genetically determined factor.
Although autoimmune thyroiditis has been reported in patients with NS, the association between this congenital syndrome and multiple autoimmune diseases has never been described in the literature. If the occurrence of autoimmune disorders in NS will be confirmed, an accurate clinical evaluation of these patients would be recommended. When there is a clinical suspicion of autoimmune phenomena, the appropriate laboratory tests (i.e., ANA, antithyroid antibodies, antiplatelet antibodies, etc.) should be performed with the aim of clarifying whether the immune system involvement in NS represents only an occasional event or is a feature of the disease.
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© 2003 Society for Adolescent Medicine. Published by Elsevier Inc. All rights reserved.
