Abstract
Ross Syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and abnormal segmental sweating. The pathophysiology of the disease remains unclear, with either hypohidrosis or hyperhidrosis reported in individual patients. We present the case of a man, aged 57 years, who presented with hyperhidrosis in his right extremities, anhidrosis in the left extremities, and changes in his pupils. The disease was not associated with markers of autoimmune disease, which supports recent research findings on the role of neurodegeneration. The patient’s son was exhibiting similar symptoms, which implicates genetic inheritance in the process. A multidisciplinary approach is crucial for the diagnosis and ultimate management of patients with Ross Syndrome.
Ross Syndrome is a rare disorder that was first reported in 1958 by Alexander T. Ross.1 It is characterized by the cardinal triad of tonic pupils, hyporeflexia, and abnormal segmental sweating with either hyper- or hypohidrosis. It is typically diagnosed in adults who are aged 30 years or older.2 The pathophysiology of the disease is still unclear, with an autoimmune etiology proposed in some cases3,4 and a neurodegenerative disease suggested by others.5 Fewer than 100 cases of Ross Syndrome have been reported in the literature.2,6,7 Here, we investigate the clinical presentation, autonomic profile, and management of a case of Ross Syndrome with concurrent hyperhidrosis and hypohidrosis.
Case Report
A man, aged 57 years, presented to the office with recent hyperhidrosis in his right arm and right leg along with swelling of the right hand and tiredness when he exercises. He had experienced intermittent episodes of hypohidrosis in the same arm and leg 3 months ago. The patient’s history dates back to more than 3 years ago, when he noticed changes in his pupils while looking at himself in the mirror as well as increased sweating over his left arm and left leg. A few months later, his sweat symptoms shifted to anhidrosis in the left arm and left leg. At the time, his symptoms were attributed to generalized dysautonomia with a suspicion for Ross Syndrome (Figure 1).
Progression of the patient’s symptoms and events across time.
During the current presentation, the patient reported that his right arm and leg had increased sweating, whereas his left arm and leg had decreased sweating. He also felt deenergized after 30 minutes of running, especially in hot environments, where he feels unable to do any kind of exercise. As a result of lack of physical activity, he gained 10 kg in one year. He further stated his eyes and mouth are often dry, which contributes to difficulties in focusing vision when changing from dark to bright environments. Other reported symptoms included several pre-syncopal episodes when he shifts position too quickly, and occasional pain in his neck and shoulders, not related to orthostatic changes. He denied any palpitations. He, however, complained of intermittent constipation and diarrhea, bloating and reflux, and intermittent urinary frequency without nocturia or erectile dysfunction. He denied bruising easily but reported healing problems.
Past medical history included having double-jointed thumbs as a child, but he denied having growing pains and never had a dislocation. He had glandular fever with a long recovery time, chicken pox at age 23 years, and an appendectomy. He had no allergies and was not taking any medication. Family history was clear of any neurological diseases, except for vascular dementia in the grandmother. His elder son has a tendency towards increased sweating, and his youngest son is hypermobile.
Vital signs were insignificant except for an elevated blood pressure, which ranged from 144/98 mmHg with 58 bpm (sitting) to 141/95 mmHg with 64 bpm (standing), with less than 2 minutes between positions. On physical examination, he had normal ocular movements with pupillomotor impairment; he had a right tonic pupil. Sensation, musculoskeletal power, and tone were normal. He exhibited right-sided hyperhidrosis and left-sided hypohidrosis (Figure 2). He was generally areflexic except for his right bicipital reflex. He was hypermobile and exhibited a positive Gorlin sign. The rest of the examination was insignificant.
Clinical symptoms of the presenting case. Segmental hyperhidrosis and sweating in the right arm and right leg and hypohidrosis in the left arm and left leg (A). Addie’s pupil upon light exposure (B).
Upon referral, the neurology consultant identified Adie’s pupil, and an impression of Ross Syndrome was made, given the background of increased hypermobility features. This further insinuated a role for excessive blood in hyperelastic blood vessels. As a result, further testing and examinations were ordered to confirm the diagnosis.
Magnetic resonance imaging of the brain ruled out any intracranial or orbital abnormalities, with normal soft tissue of the neck and cervical spinal cord noted. Cardiovascular assessment and follow up, including a tilt table test and a 24-hour ambulatory blood pressure monitor, showed no changes from baseline, describing his condition as static. Autonomic testing of plasma catecholamines were normal. Blood pressure continued to be in the higher ranges though. The patient tested negative for antinuclear antibodies and extractable nuclear antigens, negative for AMPA-1 and AMPA-2 antibodies, and negative for GABA-A, GABA-B, and ganglionic acetylcholine receptor antibodies.
A diagnosis of Ross Syndrome was made, and conservative management was planned. The patient was asked to increase water intake, to wear clothes with natural fibers, and to spray water on body parts with decreased sweating when exercising. Upon 3-year follow-up, the patient’s condition was stable.
Discussion
The patient was diagnosed with Ross Syndrome, as he presented with the triad of Addie’s pupil, hyporeflexia, and abnormal segmental sweating.1 Fatigue, heat intolerance, and increased urinary frequency are other commonly reported symptoms of the disease.2
The patient presented with left-sided hypohidrosis and right-sided hyperhidrosis. Most patients with Ross Syndrome present with one type of sweating abnormality reported in individual patients.2,8 The concurrence of hyperhidrosis and hypohidrosis is a rare manifestation of Ross Syndrome.
This report suggests that Ross Syndrome is a progressive disease. The patient reported that the hypohidrosis of his left side was preceded with hyperhidrosis on the same side that progressed into decreased sweating. Detailed history taking of the patient’s progression of symptoms is vital to understand the true etiology and symptomatology of Ross Syndrome.
The patient’s family history indicates that genetics may have a role in the etiopathogenesis of Ross Syndrome. The patient’s elder son had increased sweating, suggesting hyperhidrosis. Ross Syndrome has been reported in an identical twin pair,9 hinting at the possibility of multiple gene involvement in the development or survival of selective populations of sympathetic neurons.10
This report suggests that Ross Syndrome is rarely associated with markers of autoimmune diseases. Several case reports have documented positive autoantibodies in patients with Ross Syndrome; however, findings are not consistent between studies.3,4 In a case series of 26 patients diagnosed with Ross Syndrome, only one patient had findings of an associated systemic sclerosis.2,11 Therefore, low titer of autoantibodies has limited diagnostic potential in Ross Syndrome.
In recent years, it has been suggested that Ross Syndrome may be a new type of neurodegenerative synucleinopathy.5 The accumulation of α-synuclein has been reported in the autonomic nerve terminals in the lesser curvature of stomach of patients with Ross Syndrome.5 The patient’s reported gastrointestinal symptoms and urinary symptoms can be explained by degeneration of adrenergic fibers through the accumulation of α-synuclein. Immunofluorescence analysis reveals that gastric and urinary bladder innervation is decreased in patients with Ross Syndrome.5
A multidisciplinary approach involving neurology, cardiology, and primary care was crucial in the diagnosis and ultimate management of the patient. A conservative plan with symptomatic treatment was adopted. Immunotherapy can be used for cases with an identified associated immune-mediated disorder. However, it did not result in clinical improvement in a previously reported patient.2 Mycophenolate mofetil has also been used to treat a patient with an associated autoimmune disease, but follow-up data were not reported.11 Weight management due to physical inactivity is important to prevent associated comorbidities.
Conclusion
Ross Syndrome remains a rare pathology. This case shows that sweating abnormalities associated with the disease can include the concurrence of hyperhidrosis and hypohidrosis in the same patient. Symptoms can start long before patients seek medical attention. Therefore, detailed history taking is important to understand disease etiology and progression. Autoantibody titers are of limited diagnostic ability in Ross Syndrome, whereas the accumulation of α-synucleins in autonomic nerve terminals can be tested through neuropathology. More reports support the notion that genetics may contribute to Ross Syndrome. A personalized and interdisciplinary management plan is important to relieve disease burden and prevent worsening of symptoms.
Footnotes
Disclosure: Informed consent was obtained from the patient to publish this case report. The authors have declared they have no conflicts of interest or financial support for this work.
Author Contributions: GH and JF contributed equally to this work and are shared first authors. Conception and Design: All coauthors; Acquisition of data: All co-authors; Interpretation of data: All coauthors; Drafting of the manuscript: JF; Critical review of the draft: All coauthors; Final approval of the submitted manuscript: All coauthors.
- Received June 30, 2022.
- Revision received October 4, 2022.
- Accepted October 6, 2022.
References
- 1.↵ROSS AT. Progressive selective sudomotor denervation; a case with coexisting Adie’s syndrome. Neurology. 1958;8(11):809-817. doi:10.1212/wnl.8.11.809
- 2.↵Lamotte G, Sandroni P, Cutsforth-Gregory JK, Clinical presentation and autonomic profile in Ross syndrome. J Neurol. 2021;268(10):3852-3860. doi:10.1007/s00415-021-10531-8
- 3.↵Csak T, Folhoffer A, Horvath A, Holmes-Adie syndrome, autoimmune hepatitis and celiac disease: a case report. World J Gastroenterol. 2006;12(9):1485-1487. doi:10.3748/wjg.v12.i9.1485
- 4.↵Vasudevan B, Sawhney M, Vishal S. Ross syndrome with ana positivity: a clue to possible autoimmune origin and treatment with intravenous immunoglobulin. Indian J Dermatol. 2010;55(3):274-276. doi:10.4103/0019-5154.70694
- 5.↵Ma M, Yao J, Chen Y, Is Ross Syndrome a New Type of Synucleinopathy? A Brief Research Report. Front Neurosci. 2020;14:635. doi:10.3389/fnins.2020.00635
- 6.↵Mayer H. Bilateral tonic pupils secondary to Ross syndrome: a case report. J Optom. 2014;7(2):106-107. doi:10.1016/j.optom.2013.06.005
- 7.↵Nolano M, Provitera V, Perretti A, Ross syndrome: a rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects. Brain. 2006;129(Pt 8):2119-2131. doi:10.1093/brain/awl175
- 8.↵Mullaaziz D, Kaptanoglu AF, Eker A. Hypohidrosis or hyperhidrosis? Ross syndrome. Dermatologica Sinica. 2016;34(3):141-43. doi: https://doi.org/10.1016/j.dsi.2015.10.004
- 9.↵Nolano M, Provitera V, Donadio V, Ross syndrome: a lesson from a monozygotic twin pair [published correction appears in Neurology. 2013 Nov 12;81(20):1803]. Neurology. 2013;80(4):417-418. doi:10.1212/WNL.0b013e31827f08d7
- 10.↵Luther JA, Birren SJ. Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties. Auton Neurosci. 2009;151(1):46-60. doi:10.1016/j.autneu.2009.08.009
- 11.↵Lamotte G, Sandroni P. A case of Ross syndrome associated with systemic sclerosis. Clin Auton Res. 2021;31(3):463-465. doi:10.1007/s10286-021-00773-x
