A Collection of Heritable and Autoimmune Connective Tissue Disorder Manifestations
Mario Madruga, MD, Mark Wallace, MD, Angela Wabulya, MD, Na’im Fanaian, MD, and Mary Hilal, MD
For 3 days, a 28-year-old woman with a history of polymyositis and possible dermatomyositis had fever, chills, and a nonproductive cough. She complained of rash, joint pain, and progressive immobility because of severe muscle weakness.
History. For the past 6 years, she had been taking prednisone (60 mg/d), hydroxychloroquine (200 mg twice daily), and tramadol (100 mg every 6 hrs as needed for pain).
Physical examination. The patient’s vital signs were normal. She had moon facies, and crackles were heard bilaterally in the lower lung fields. She had diffuse violaceous, desquamative plaques (Figure 1) in the antecubital fossae and on the posterior aspect of the knees and thighs (Figure 2). There was no evidence of Gottron papules.
Other than an aspartate aminotransferase level of 82 U/L, results of a chemistry panel were normal. The initial white blood cell count was 11,000/µL, with 77% neutrophils. The hemoglobin level was 8.8 g/dL, and the platelet count was 249 × 103/µL. The erythrocyte sedimentation rate was 110 mm/h, lactate dehydrogenase was 717 U/L, and creatine kinase was
Results of multiple blood and urine cultures were negative. The patient was positive for antinuclear antibodies (1:640), anti-Jo-1 antibodies, and anti-ribonucleoprotein antibodies. The aldolase level was mildly elevated. Test results for SSA antibodies and SSB antibodies were positive; results for anti-Smith antibodies, anti-dsDNA antibodies, and anti-Scl-70 antibodies were negative. HIV testing yielded negative results.
Laboratory testing. The patient’s condition continued to deteriorate over 4 days despite appropriate therapy; skin lesions, myopathy, and dyspnea worsened. Cultures of 3 skin biopsy specimens taken from the upper extremities revealed numerous budding yeast organisms (Figure 3) that grew mold forms of Histoplasma capsulatum. Microscopy of a muscle biopsy specimen taken from the right lower limb demonstrated fungal yeast forms; it also showed type 2 fiber atrophy, which likely was secondary to long-term high-dose corticosteroid therapy. A urine test for Histoplasma antigen was positive (27.84 ng/mL).
Based on analysis of the serologic data, it was concluded that the patient likely had mixed connective-tissue disease with disseminated histoplasmosis rather than dermatomyositis.
Discussion. Histoplasmosis is the most prevalent endemic mycosis in the United States. The diagnosis can be challenging and requires a high index of suspicion. A multidisciplinary approach and specific tests aid in a timely diagnosis. Most infections are asymptomatic. However, acute pulmonary infection or severe and progressive disseminated disease may develop in some patients. Risk factors include extremes in age and immunodeficiency.1,2
Treatment. For severe disseminated histoplasmosis, amphotericin B is the initial drug of choice. Most patients respond quickly to amphotericin B and subsequently can be treated with itraconazole. Therapy for at least 6 to 48 weeks is preferred because it may reduce the risk for relapse. Long-term maintenance therapy may be needed in immunocompromised patients and in those who experience relapse after treatment.
Outcome of the case. After a 2-week course of intravenous amphotericin B lipid complex, the patient made a remarkable recovery; rash and muscle pain diminished within 9 days (Figure 4). The prednisone dosage was tapered slowly during the hospital stay. The patient was discharged with a 6-month regimen of itraconazole and trimethoprim-sulfamethoxazole, which was to be taken as long as she continued to take prednisone.
- Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore). 1980;59(1):1-33.
- Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine (Baltimore). 1983;62(5):263-270.
Late Postpartum Eclampsia With Posterior Reversible Encephalopathy Syndrome (PRES)
Matthew P. Sistiki, MD, and Richart W. Harper, MD
A 37-year-old woman with a 2-year history of migraine headaches presents to the emergency department with a new-onset seizure.
Two days earlier, the patient had complained of a headache that was similar in quality to her previous migraines. One day earlier, she had experienced blurred vision and a decrease in hearing; these symptoms were atypical of her migraines. On the day of admission, her spouse witnessed seizure-like activity of 10 seconds’ duration with loss of bladder control. During emergency services transport, the patient had a generalized seizure.
History. Findings of a previous evaluation of her headaches 2 years earlier,
including a computed tomography angiogram of her head, were unremarkable. Hypertension had been diagnosed when she was in her 20s. She had had an uncomplicated pregnancy at age 20 and an uncomplicated cesarean delivery of twin girls 16 days before this admission. Her only medication was a folate supplement.
Physical examination. Findings were as follows: temperature, 37.3°C; heart rate, 119 beats/min; blood pressure, 201/107 mm Hg; respiratory rate, 15 breaths/min; oxygen saturation, 97% on room air. The patient appeared lethargic. Pupils were reactive to light bilaterally. The remainder of the neurologic examination findings were unremarkable. The neck was supple without cervical rigidity. Heart and lung sounds were normal. Her abdomen had a healing surgical wound. Extremities and skin were normal.
Her white blood cell count was 14,800/µL with a normal differential. Her red blood cell count and platelet count were normal. Serum chemistry, liver function, and coagulation test results were normal. Urinalysis revealed a protein level of greater than 500 mg/dL. The Figure shows aT2 fluid-attenuation inversion recovery image from an magnetic resonance imaging scan.
Discussion. Eclampsia is the onset of seizures in the presence of the preeclampsia syndrome. Gestational hypertension, proteinuria, and edema define the classic triad of preeclampsia, although more recent studies suggest that not all 3 signs need be present. Even hypertension need not always be present when other signs and symptoms are found. Headache, blurred vision, abdominal pain, and mental status alterations may herald the onset of preeclampsia/eclampsia.1 Eclampsia should be strongly considered in any peripartum woman who presents with new-onset seizures, proteinuria, or hypertension. Risk factors for eclampsia include age over 35 years, first pregnancy, chronic hypertension, diabetes, renal disease, preeclampsia, multiparous pregnancy, and obesity. Laboratory abnormalities include proteinuria (30 mg/dL or higher, or 300 mg/24 h or higher).
Most cases of eclampsia occur after 28 weeks of gestation and within 48 hours of delivery; however, cases occurring outside this timeframe have been well described. Late postpartum eclampsia, as was seen in this patient, has been observed up to 4 weeks postpartum. Any presentation that is somewhat atypical (eg, atypical gestation age, atypical focal neurologic signs) warrants further investigation, including lumbar puncture and radiologic imaging.2,3
PRES is a distinct radiologic pattern of vasogenic edema in the setting of neurotoxicity that is strongly associated with eclampsia. The syndrome is distinguished by its focal, symmetric distribution in watershed areas of the parietal and occipital areas of the brain. Contrary to the name, PRES also can affect frontal, brainstem, or cerebellar zones. Symptoms associated with PRES include headaches, vision changes, focal neurologic signs, alterations in mental status, and seizures. PRES is not unique to eclampsia and is observed in a number of other conditions (Table). PRES is thought to be fully reversible with management of the underlying disorder.4,5
Treatment. Magnesium sulfate is the mainstay of treatment to prevent recurrent eclamptic convulsions. In head-to-head and collaborative trials, magnesium infusion continued for 24 hours after
delivery or the last seizure was more efficacious than phenytoin, nimodipine, or benzodiazepines.6 Elevated systemic blood pressure is managed with antihypertensives. Adequate placental perfusion pressure takes priority over returning patients to normotensive levels. When the onset of preeclamptic symptoms is gradual, preventive therapy includes preemptive treatment of hypertension and prophylactic magnesium.1,2
Outcome of the case. Given the patient’s hypertension, recent delivery, and proteinuria, eclampsia was strongly considered in the differential, and magnesium and antihypertensives were started. The late onset of symptoms (16 days postpartum) warranted radiographic imaging. A 24-hour urine protein collection demonstrated 1107 mg of protein/24 hrs (normal, 25 to 75 mg/24 hrs), which strongly supported the diagnosis of eclampsia. She had no further seizures.
- Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402-410.
- Sibai BM, Stella CL. Diagnosis and management of atypical preeclampsia-eclampsia. Am J Obstet Gynecol. 2009;200(5):481.e1-481.e7.
- Matthys LA, Coppage KH, Lambers DS, Barton JR, Sibai BM. Delayed postpartum preeclampsia: an experience of 151 cases. Am J Obstet Gynecol. 2004;190(5):1464-1466.
- Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008;29(6):1036-1042.
- Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29(6):1043-1049.
- Euser AG, Cipolla MJ. Magnesium sulfate for the treatment of eclampsia: a brief review. Stroke. 2009;40(4):1169-1175.
Scott D. Olewiler, MD
For the past 2 weeks, a 46-year-old woman had had malaise, myalgia, and hand and elbow arthralgia. Twelve hours before she was hospitalized, red spots had started to appear on her shins and thighs. Soon afterward, her left ankle had become increasingly painful, tender, and warm.
History. The patient had never used intravenous drugs, and she was not currently sexually active. Her temperature was 38.5°C. The rash consisted of 3- to 5-mm macules, nonblanching and roughly circular, scattered mainly on the pretibial areas and the medial surface of her thighs. Her left ankle was warm, red, swollen, and painful with any joint motion.
On admission, ceftriaxone and vancomycin were administered empirically; these were discontinued 2 days later, when all microbiologic assays proved negative for pathologic organisms. Joint fluid and blood cultures were sterile. Pharyngeal, rectal, and uterine cervical cultures were negative for gonococcus, and serology for hepatitis B was unreactive. Skin biopsy on the second day of hospitalization confirmed the presence of leukocytoclastic vasculitis.
Discussion. Leukocytoclastic (so called because of the apparent fragmentation of neutrophilic nuclei) vasculitis is a neutrophilic inflammation of small blood vessels. A number of disease processes, grouped collectively as “hypersensitivity vasculitis,” cause this type of vessel inflammation, which predominantly affects the postcapillary venule.
Purpura, malaise, myalgia, and fever are the presenting symptoms of hypersensitivity vasculitis. Oligoarthritis or monarthritis is present in 40% of cases. Three diagnostic points are pertinent concerning the rash:
- The purpura is nonblanching; this indicates extravasation of blood from the inflamed postcapillary venules.
- The crops of circular purpura prefer dependent areas of the body; they typically are found on the legs, thighs, and buttocks in symmetric distribution.
- The shape of the individual macule is regular and approximately circular, because erythrocytes exude radially in all directions from the inflamed and damaged venules.
The last feature is in sharp contrast to arteritis, in which lesions have highly irregular margins that represent areas of skin infarction caused by vasculitic and thrombotic occlusion of the arterioles. Although Wegener granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, and some infections may cause palpable purpura, the macules caused by these disorders would typically have irregular margins because they represent actual arteritic infarction rather than venular “ooze.”
Leukocytoclastic vasculitis has a benign course because it usually is confined to the skin. It may, however, be closely mimicked by several serious diseases; for example, purpuric lesions and arthritis may appear in patients who have chronic hepatitis B infection, bacterial endocarditis, disseminated gonococcal infection, or meningococcemia.
Arthrocentesis should be done to rule out a joint infection in any patient with acute monarthritis. Because of the concern for meningococcemia and septic arthritis, empiric antibiotic therapy may be advisable until definitive data are available.
Finally, even if the diagnosis of leukocytoclastic vasculitis is made, this may also be a feature of leukemia, lymphoma, systemic lupus erythematosus, rheumatoid arthritis, or Sjögren syndrome.
Outcome of the case. The patient was given ibuprofen, and all her symptoms resolved. By the fourth day, she was able to walk freely, and her skin lesions had disappeared. She had no recurrence 5 months after discharge and no longer required medication.
Piezogenic Pedal Papules
Emily Rubenstein, DO, Angela Combs, DO, and Eduardo Weiss, MD
These grouped, white to flesh-colored papules on the plantar aspect of a 28-year-old woman’s heels appeared during weight bearing and disappeared in non-weight-bearing positions. The patient, a nurse whose work required standing for hours, had noticed the lesions about a year earlier. Her medical history was unremarkable, and she was taking no medications. Her sister had similar lesions on her heels.
Piezogenic pedal papules are common and benign; they result from fat herniation through the dermis. They occur in up to 80% of the population and usually are asymptomatic.1 Occasionally, the papules are painful. The pain has been associated with fat necrosis caused by a lack of blood supply from compression. Piezogenic papules also can occur on the wrists and can be either asymptomatic or painful. Management is the same for both locations.
Discussion. Piezogenic papules show no race predilection and can occur at any age, including infancy. They have been reported more frequently in women. Familial association has been reported, although most often it is unrelated.
The papules have been associated with Ehlers-Danlos syndrome.2 An increased incidence has been noted with obesity, excessive weight-bearing exercise, and flatfoot, although the condition most often is idiopathic. Conditions that may mimic piezogenic pedal papules include xanthomas, tophi, skeletal abnormalities, and infantile pedal papules.3
Usually a clinical diagnosis, piezogenic papules warrant further workup in patients with signs and symptoms of Ehlers-Danlos syndrome, such as hypermobile joints. Imaging may be necessary if orthopedic abnormalities are suspected.
Treatment. No treatment is required for asymptomatic lesions. For painful papules, restriction of excessive weight-bearing activity, orthotics, surgical excision, and intralesional corticosteroid injections have been used.4
- Zaidi Z, Jafri N, Noori B, Thawerani H. Piezogenic papules: a study of 100 cases. J Pak Med Assoc. 1995;45(4):93-94.
- Kahana M, Feinstein A, Tabachnic E, Schewach-Millet M, Engelberg S. Painful piezogenic pedal papules in patients with Ehlers-Danlos syndrome. J Am Acad Dermatol. 1987;17(2 pt 1):205-209.
- Greenberg S, Krafchik BR. Infantile pedal papules. J Am Acad Dermatol. 2005;53(2):333-334.
- Doukas DJ, Holmes J, Leonard JA. A nonsurgical approach to painful piezogenic pedal papules. Cutis. 2004;73(5):339-340, 346.