Purkinje cell cytoplasmic antibody type 1 (PCA-1)–IgG (or anti-Yo) is characteristically detected in women with gynecological or breast adenocarcinoma. We describe 2 unique scenarios occurring in 1 patient: PCA-1 paraneoplastic autoimmunity in a child, and a paraneoplastic neurological disorder in the context of Down syndrome.
A child with Down syndrome and a history of adrenocortical carcinoma resected at age 1 year presented at age 7 years with cerebellar ataxia of subacute onset. Paraneoplastic serological and cerebrospinal fluid evaluations revealed PCA-1. Serological and biochemical studies also supported a diagnosis of subclinical autoimmune hypothyroidism. Extensive serum, urine, and radiological testing did not reveal a new or recurrent neoplasm. Neurological improvements after standard immunotherapy were lacking.
Conclusions and Relevance
Solid organ neoplasms are uncommon among patients with Down syndrome, but organ-specific autoimmune diseases are common. In our patient, Down syndrome–related impaired T regulatory lymphocyte function (previously reported) may have resulted in both enhanced immunity against an undetected solid neoplasm and paraneoplastic neurological (PCA-1) autoimmunity.
Purkinje cell cytoplasmic antibody type 1 (PCA-1)–IgG (or anti-Yo) is characteristically detected in women with adenocarcinoma of müllerian tract (ovary, fallopian tube, peritoneal surface, or endometrium) or breast diagnosed in a paraneoplastic neurological context.1,2 Affected patients present with the subacute onset of neurological symptoms, commonly (but not exclusively) cerebellar ataxia.2 Any neoplasm detected is usually limited stage and amenable to treatment. In contrast, improvements with immunotherapies are usually limited and neurological outcomes are generally poor. Pathological and cellular immunological studies have implicated cdr2 antigen–specific CD8+ cytotoxic T lymphocytes as major effectors.2,3 Herein, we report PCA-1 autoimmunity in a child with Down syndrome.
A 7-year-old girl with Down syndrome presented with a 3-week history of worsening unsteady gait. At age 1 year, she was investigated for precocious puberty. An abdominal mass detected radiologically was identified at surgery as a left adrenal cortical tumor with local soft-tissue infiltration. Histological analysis revealed adrenocortical carcinoma with periadrenal extension but no lymph node involvement. Successful treatment consisted of surgical resection alone. The patient’s father died at age 27 years of glioblastoma multiforme. The maternal grandmother had breast adenocarcinoma in her fifth decade of life.
Physical examination at age 7 years demonstrated a facial appearance characteristic of Down syndrome. She had no change in mental status or behavior noted. She had cerebellar-type gait ataxia, falling easily on turning, without appendicular signs or dysarthria. Cranial nerve testing results were unremarkable. Motor testing demonstrated mild hypotonia but normal strength. Deep tendon reflexes were normal in upper extremities and reduced in lower extremities. Plantar reflexes were flexor bilaterally. Sensory examination findings were normal.
Brain magnetic resonance imaging demonstrated moderate generalized cerebral and cerebellar atrophy. Findings on magnetic resonance imaging of the entire spine, electromyography, and nerve conduction studies were normal. Initial laboratory evaluations demonstrated a normal complete blood cell count and differential white blood cell count, positive thyroid peroxidase antibody (37.9 IU/mL; reference range, <9.0 IU/mL) and thyroglobulin antibody (415 IU/mL; reference range, <116 IU/mL), and evidence of subclinical hypothyroidism (thyroid-stimulating hormone, 11.6 mIU/L; reference range, 0.465-4.827); her free thyroxine level was within normal limits. Cerebrospinal fluid testing revealed normal protein, normal white blood cell count, and 6 cerebrospinal fluid–exclusive oligoclonal bands (reference range, <4). Paraneoplastic serological evaluation (Mayo Medical Laboratories) revealed PCA-1–IgG by immunofluorescence screening on cryosectioned mouse brain2 (end-point dilutions: serum, 1:15 360 [reference range, undetected at 1:240]; cerebrospinal fluid, 1:256 [reference range, undetected at 1:2]) (Figure). These findings were confirmed by Western blot (Figure). Glutamic acid decarboxylase 65 (GAD65)–IgG also was detected (0.15 nmol/L by radioimmunoprecipitation assay; reference range, <0.03 nmol/L). There was no biochemical or imaging evidence of neoplasia: urinary vanillylmandelic acid and homovanillic acid levels, whole-body magnetic resonance imaging and positron emission tomographic findings, and metaiodobenzylguanidine-based scintigraphy findings were all normal. Exploratory surgery for occult neoplasm was not undertaken.
Indirect immunofluorescence images show discrete cytoplasmic binding of Purkinje cell cytoplasmic antibody type 1 (PCA-1)–IgG in mouse tissues. A, Purkinje (P), molecular layer (M), and Golgi (G) neurons in cerebellar cortex (scale bar = 40 µm). B, Midbrain neurons (scale bar = 40 µm). C, Ganglionic and myenteric plexus neurons (scale bar = 40 µm). D, Western blot demonstrates PCA-1–IgG binding to a 52-kDa, reduced, denatured protein in an aqueous rat cerebellar cortical extract. A healthy control’s serum IgG is nonreactive. Control IgG in serum of a patient who is seropositive for antineuronal nuclear antibodies (ANNA-1)–IgG (anti-Hu) binds to a characteristic series of 35- to 40-kDa proteins.
During the 9 months of follow-up available, the patient’s motor disorder did not improve despite treatment with intravenous immunoglobulin, intravenous methylprednisolone, and oral prednisone taper.
To our knowledge, the occurrence of a paraneoplastic neurological disorder in a patient with Down syndrome as well as the pediatric age of this PCA-1–IgG-positive case are both unique observations in the literature. The patient presented with cerebellar ataxia, which did not improve with immunotherapy, as is typical of PCA-1 autoimmunity in which histological and in vitro immunological studies have demonstrated early neuronal loss mediated by cytotoxic CD8+ T lymphocytes.2,3 Autoantibodies specific for intracellular antigens generally lack pathogenicity for intact cells.
The risk of acute leukemias is recognized to be increased 10- to 20-fold in patients with Down syndrome (susceptibility genes are located in the long arm of chromosome 21), but the risk of solid neoplasms is reported to be reduced.4 In contrast, this child had adrenal carcinoma (not previously reported with PCA-1) 5 years before neurological symptom onset and had a family history of solid neoplasms. Although no neoplasm was detected at the time of neurological presentation, it is possible that she had an occult reoccurrence of the adrenal carcinoma or had a new occult gynecological or breast adenocarcinoma.
As well as having an unusually high risk for solid neoplasm, this patient also had an abnormal immunological background. Several autoimmune diseases (eg, celiac disease, thyroid disorders, and type 1 diabetes mellitus5) are reported disproportionately in patients with Down syndrome, and indeed our patient was additionally seropositive for thyroid antibodies and GAD65-IgG. The detection of GAD65-IgG (0.15 nmol/L) and thyroid autoantibodies was consistent with a predisposition to organ-specific nonneurological autoimmunity (including thyroid disease, type 1 diabetes mellitus, and pernicious anemia) rather than neurological disease. Levels of GAD65-IgG in patients with nonparaneoplastic autoimmune neurological disorders usually exceed 20 nmol/L.6
The thymus glands of infants with Down syndrome are architecturally and functionally abnormal and exhibit impaired T-lymphocyte maturation.7,8 It is further reported that natural (thymic) T regulatory lymphocytes in patients with Down syndrome have reduced suppressive activity against autoreactive T lymphocytes.5 We therefore speculate that in our patient, impaired T regulatory lymphocyte function may have resulted in both enhanced immunity against an undetected solid neoplasm, either recurrent or new, and paraneoplastic neurological (PCA-1) autoimmunity. It is also plausible that this child’s personal and family history of solid neoplasms and her earlier documented precocious puberty may have promoted development of an occult müllerian or breast adenocarcinoma. In this immunological, genetic, and hormonal context, a dysregulated cdr2-specific immune response may have restrained the growth of an adenocarcinoma at the expense of neurological autoimmunity.
Corresponding Author: Andrew McKeon, MD, Neuroimmunology Laboratory, Hilton 3-79, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email@example.com).
Accepted for Publication: July 26, 2013.
Published Online: January 13, 2014. doi:10.1001/jamaneurol.2013.4551.
Author Contributions: Dr McKeon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Pranzatelli, Lennon, McKeon.
Acquisition of data: Philipps, Alisanski, Pranzatelli, Clardy, McKeon.
Analysis and interpretation of data: Alisanski, McKeon.
Drafting of the manuscript: McKeon.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, and material support: Philipps, Clardy, Lennon.
Study supervision: McKeon.
Conflict of Interest Disclosures: Dr Philipps has received compensation from Lundbeck Pharmaceuticals within the past year for consultative work. Dr Pranzatelli receives research support from the Spastic Paralysis Research Foundation (Illinois–Eastern Iowa District), Kiwanis International, Ronald McDonald Charities of Central Illinois, and Questcor Pharmaceuticals. Dr Lennon receives research support as grant RO1-NS065829 from the National Institutes of Health and is named inventor on 2 patent applications filed by Mayo Foundation for Medical Education and Research that relate to neuromyelitis optica (NMO; aquaporin 4 [AQP4]) antibody and its application to cancer and functional assays for detecting AQP4-IgG. A patent issued for technology related to NMO-IgG testing has been licensed to a commercial entity. Dr Lennon and Mayo Clinic have received royalties that exceed the federal threshold for significant financial interest from licensing of this technology and have rights to receive future royalties. Serological testing for neural autoantibodies is offered on a service basis by Mayo Collaborative Service, Inc, an agency of Mayo Foundation. Neither Dr Lennon nor her laboratory benefit financially from this testing. Dr McKeon receives research support from the Guthy-Jackson Charitable Foundation. No other disclosures were reported.
Philipps G, Alisanski SB, Pranzatelli M, Clardy SL, Lennon VA, McKeon A. Purkinje Cell Cytoplasmic Antibody Type 1 (Anti-Yo) Autoimmunity in a Child With Down Syndrome. JAMA Neurol. 2014;71(3):347-349. doi:10.1001/jamaneurol.2013.4551