Age: 17.0
Sex: F
Vaccine: HPV4, HPV9
Symptoms: Epistaxis, Factor Xa activity test, Fatigue, Feeling cold, Femoral bruit
Clinical narrative: Mast Cell Activation Syndrome; Postural orthostatic tachycardia syndrome; This literature marketed information has been received from the authors in a published article title as stated below and refers to a 17-year-old female patient.  Her current conditions included premature twin delivery, mild early developmental delay. Frequent idiopathic spontaneous epistaxis since 8 years old. Bilateral knee pain since age 10, attributed to Osgood-Schlatter disease. At 16 year old, erythromycin was started to treat acne but did not help; two months later, her feet became erythematous and blistered and started "burning from the inside out". Family history was notable for a mother with sarcoidosis and suspicions of  Mast Cell Activation Syndrome (MCAs), a sister who had Stage II nodular sclerosing Hodgkin lymphoma and quickly achieved a remission which had persisted ever since but who was also now suspected of also having MCAS, a maternal grandfather who had a brain aneurysm, a maternal grandmother who had bladder cancer, paternal grandparents who were healthy, a father who was healthy, and two other siblings who both had hypermobile Ehlers Danlos Syndrome (hEDS). The patient denies any history of smoking, significant alcohol use, or illegal substance use. She denied any known drug allergies.  On an unknown date, the patient was vaccinated with a dose of unidentified Merck hpv vaccine administered, also reported as Gardasil (Lot #, expiration date, dose, route of administration and anatomical location of vaccine were not reported) for prophylaxis vaccination.   On an unspecified date, about six weeks after her first Gardasil vaccination (which she had appeared to acutely tolerate without difficulty), one night, "out of the blue", she started suffering palpitations and pulsatile tinnitus. Her mother, a nurse, checked her pulse the next morning and found it to be about 160; the patient also was flushed at the time. About 30 seconds into that pulse count, there was a sudden pause in the tachycardia, at which point the patient suffered an acute full syncope. She was taken to a nearby emergency department (ED). While there, she continued suffering waxing/waning flushing. While on a heart monitor, she was manifesting multiple runs of non-sustained ventricular tachycardia, which were witnessed only by the patient's mother. She also was hypertensive, about 140/90. Orthostatic hypotension testing was positive. She was admitted to the hospital. An echocardiogram was unremarkable. A consulting cardiologist suspected postural orthostatic tachycardia syndrome (POTS), which did not entirely make sense to the patient's mother since there clearly was some non-orthostatic component to the cardiac issues. She was referred to a nephrologist (because of the hypertension) to rule out a pheochromocytoma, but testing (principally an ultrasound and blood and urine testing) was all negative except for a slight increase in norepinephrine. Many more symptoms came on in the days and weeks beyond that point, including chest pain and palpitations, numbness and tingling in her distal extremities, tremors, difficulty focusing her vision, cognitive dysfunction (especially memory, also occasionally almost catatonic, according to her mother), insomnia, anorexia, diffusely migratory joint and bone pain, and severe fatigue. There were times when she could barely walk because of all of these symptoms. About five months after the initial syncope, she finally was able to consult with a neurologist, and she was immediately suspected of having hypermobile Ehlers Danlos Syndrome (hEDS). She had a 9/9 Beighton score and was diagnosed with hEDS. Her neurologist also shortly suspected she also had a mast cell activation syndrome (MCAS) and referred her to an immunologist to investigate this suspicion. Meanwhile, she was empirically started by the neurologist on guanfacine. On the second day of this trial, she developed acute numbness of the bilateral calves and toes. The guanfacine was immediately stopped by the neurologist. She also was then started on cetirizine (ZYRTEC) and ranitidine (ZANTAC) and oral Cromoglicic acid (CROMOLYN).  She also underwent a tilt table test which showed "possible" hyperadrenergic postural orthostatic tachycardia syndrome (hyperPOTS), with her blood pressure peaking around 190/103, causing significant acute visual disturbance. She then consulted with an immunologist for evaluation of suspected MCAS, who felt her presentation was consistent with MCAS but was unsure how to proceed with diagnostic testing. The patient did not think that Cromoglicic acid (CROMOLYN) was helping, so it was stopped and ketotifen was added. The immunologist then performed skin patch food allergy testing on her, finding an extensive array of positives, and yet she knew she did not react to any of the foods which showed positive reactivity on the testing. Also, she was beginning to find an increasing array of modest stimuli which were provoking flares of flushing and other symptoms. She started developing sensitivities to various odors, and in 1/18 she was exposed to a car air freshener and acutely developed hives, headache, flushing, dyspnea, and throat numbness. She returned to the immunologist and was prescribed montelukast 10 mg once daily plus an epinephrine autoinjector as needed for anaphylaxis. She improved only slightly once montelukast was started. Within a few months, her array of symptoms had worsened to the point where she could not walk more than a hundred feet without having to sit and rest. She was continuing to suffer chest pain, tachycardia, and palpitations with even the slightest exertion. She soon consulted an electrophysiologist. A Holter monitor led to a diagnosis of inappropriate sinus tachycardia (IST). She was started on diltiazem and midodrine, which helped her fatigue somewhat (she was now able to walk a bit longer before requiring rest) but not the other symptoms. Her local physicians at this point, seeing little improvement, wanted to start weaning her off some of her medications, but her mother was concerned this would leave the patient even more debilitated. At this point (especially with the patient having just gotten bone densitometry which suggested osteopenia despite there being no apparent cause), her mother began wondering whether other diagnostic and therapeutic efforts might be needed about the patient's clinically diagnosed MCAS. Her chief complaints at the time of initial evaluation were episodes of chest pain, cognitive dysfunction, joint pain, and epistaxis. Her mother further noted that when the patient suspended her antihistamines to undergo allergy testing, she developed another episode of epistaxis that very night.  On a full review of systems at the initial evaluation, although she denied any issues with diaphoresis, irritation of the eyes/nose/mouth/throat, easy bleeding (other than epistaxis), sinonasal congestion, coryza, post-nasal drip, dysphagia, wheezing, gastroesophageal reflux, vomiting, diarrhea, constipation, abdominal discomfort/pain, bloating, genitourinary problems, edema, dental/gingival problems, onychodystrophy, she endorses a wide range of other, chronic/recurrent, episodic/intermittent and/or waxing/waning issues including subjective (rarely objective) fevers, flushing, feeling cold some of the time, fatigue (often to the point of exhaustion), malaise, headaches, diffusely migratory aching/pain, diffusely migratory pruritus, unprovoked fluctuations in weight, poor appetite, acute brief inability to focus vision, tinnitus, epistaxis, easy bruising, dyspnea with flares, palpitations, non-anginal chest discomfort/pain, nausea, diffusely migratory weakness, diffusely migratory tingling/numbness (typically about the distal extremities), diffusely migratory bilateral cervical adenopathy and adenitis, orthostatic and non-orthostatic presyncope, syncope twice (the unprovoked incident detailed above and once more at the time of a blood draw), cognitive dysfunction (particularly memory, concentration, and word-finding), possible hair loss, diffusely migratory rashes (typically patchy macular erythema, and particularly about the toes with associated burning), hives, insomnia, nonrestorative sleep, suspected (but not yet formally diagnosed) anxiety and depression, modest joint hypermobility (she spontaneously demonstrated a Beighton score of only 4/9 at the thumbs and little fingers), unusually vigorous reactions to insect bites, and poor healing in general.  At the time of the initial evaluation, the patient listed her current medications as diltiazem 30 mg thrice daily, ranitidine 150 mg twice daily, cetirizine 10 mg twice daily, midodrine 5 mg twice daily, hydroxyzine 25 mg as needed, compounded oral ketotifen 1 mg twice daily, and montelukast 10 mg once daily.   Physical examination at the initial evaluation was found a modestly acneiform and vaguely tired-appearing but otherwise outwardly healthy appearing, trim young woman in no acute distress, pleasant, cooperative, fully alert and oriented, easily independently ambulatory, presenting with her ppropriately concerned and supportive mother. Vital signs were notable for blood pressure 128/93, pulse 95, weight 105 pounds. Key findings were her mildly tired/acneiform but otherwise comfortable general appearance, head/ears/eyes/nose/throat (HEENT) benign, no plethora/ pallor/ diaphoresis/ jaundice/ bleeding/ bruising, a modest extent of migratory waxing/waning small-patchy macular erythematous rash scattered about the anterior neck, supple, no jugular venous distention (JVD) or thyromegaly or carotid/abdominal/renal bruits (but she did have mild bilateral femoral bruits), no palpable adenopathy or tenderness at any of the usual node-bearing sites, clear lungs, regular heart with no adventitious sounds, abdomen completely benign, zero peripheral edema, and the neurologic examination, too, was unremarkable. No costovertebral angle or spinal column tenderness was evoked on palpation and percussion about these areas. On a light scratch test on the upper back, moderately bright dermatographism (erythroderma only, no hives) quickly emerged but was beginning to resolve when last checked 10 minutes later.  Laboratory testing for mast cell activation was positive for a 24-hour urinary prostaglandin D2 level elevated at 777 ng (normal 100-280) and a plasma heparin level elevated at 0.07 anti-Factor Xa units/ml (upper normal 0.02).  Trials of various non-sedating H1 blockers and various H2 blockers found loratadine and ranitidine served her better than the others, having gained her a broad range of symptomatic improvements at follow-up three months after initial evaluation. She was subsequently lost to follow-up.     Literature report:   Upon internal review the of Mast Cell Activation Syndrome (MCAs) was considered as medically significant.   This is one of several report from the same literature article.   A copy of the published article is attached as further documentation of the patient's experience.