28 Zdrav Vestn | januar – februar 2017 | Letnik 86 MetaboLne in horMonske Motnje 1 University Children’s Hospital, University Medical Centre Ljubljana, Slovenia 2 Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia 3 Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia Korespondenca/ Correspondence: r ok orel, e: rok.orel@kclj.si Ključne besede: disfagija; požiralnik; krikofaringealna ahalazija; avtoimunost; dilatacija Key words: dysphagia; esophagus; cricopharyngeal achalasia; autoimmunity; dilatation Citirajte kot/Cite as: Zdrav Vestn. 2017; 86(1–2):28–33 Zdrav Vestn | januar – februar 2017 | Letnik 86 Metabolne in hormonske motnje klinični primer Cricopharyngeal achalasia in connection with autoimmune disorders in a pre- adolescent patient: A case report Krikofaringealna ahalazija v povezavi z avtoimunskimi boleznimi v obdobju predadolescence: Prikaz primera Urška Vučina, 1 Primož kotnik, 2 r ok orel 3 Abstract Cricopharyngeal achalasia is an uncommon cause of dysphagia, especially in children. Congenital form is known in neonates and infants. In older children this disease has been reported in very rare cases and mostly in connection with neurological and muscular diseases. We present a case of a 12-year-old girl with a four-year history of dysphagia. Esophagogastroduodenoscopy, radiological contrast swallow study and esophageal manometric study confirmed the diagnosis of cricopharyn- geal achalasia. The patient was successfully treated with dilatation of the upper esophageal sphincter. An initial attempt of dilatation appears to be a safe and effective option in the management of crico- pharyngeal achalasia in children, and may prevent or at least postpone the need for myotomy. Fol- lowing the diagnosis of cricopharyngeal achalasia, several autoimmune conditions were diagnosed. Our case report revealed that cricopharyngeal achalasia may occur in association with some other autoimmune conditions, and that autoimmunity may also play a role in cricopharyngeal achalasia itself. Izvleček Krikofaringealna ahalazija je pri otrocih izjemno redek razlog za disfagijo. Poznana je kongenital- na oblika krikofaringealne ahalazije pri novorojenčkih in dojenčkih, pri starejših otrocih pa so to bolezen doslej opisali zelo redko in večinoma v povezavi z nevrološkimi in mišičnimi boleznimi. V prispevku prikazujemo primer 12-letne deklice s štiriletno anamnezo disfagije. Z ezofagogastroduo- denoskopijo, radiološko preiskavo požiranja s kontrastom in ezofagealno manometrijo smo potrdili diagnozo krikofaringealna ahalazija. Bolnico smo uspešno zdravili z dilatacijo zgornjega ezofage- alnega ustja. Začetni poizkus zdravljenja z dilatacijo se zdi varna in učinkovita metoda zdravljenja krikofaringelane ahalazije pri otrocih in lahko prepreči ali vsaj odloži potrebo po miotomiji. Po po- stavitvi diagnoze krikofaringealna ahalazija smo pri bolnici diagnosticirali več avtoimunskih motenj. Opisan primer prikazuje povezavo pojava krikofaringelane ahalazije z avtoimunskim dogajanjem in možnost, da bi lahko bil tudi avtoimunski proces eden od razlogov za pojav krikofaringealne ahalazije. Introduction Dysfunction of upper esophageal sphincter (UES) motility is an infrequent cause of dysphagia in the pediatric po- pulation. Evaluation of motor dysfunc- tion of the pharyngo-esophageal junc- tion suggests two main defects of UES Cricopharyngeal achalasia in connection with autoimmune disorders in a pre-adolescent patient: a case report 29 kLinični PriMer Prispelo: 12. 5. 2016 sprejeto: 11. 12. 2016 motility: abnormalities in the sphincter resting pressure and abnormalities in the UES relaxation  (1,2). Patients with cricopharyngeal achalasia show incom- plete UES relaxation after majority of swallows (1,3). Symptoms usually inclu- de dysphagia, food regurgitation, coug - hing, aspiration pneumonia, and weight loss. There is a functional narrowing in the region of the UES. Since the first de- scription by Chevalier Jackson in 1915 and the first series of patients by Kelly in 1919, this disorder has been frequently observed in adult patients, predominan- tly secondary to neurologic and muscu- lar disorders, previous neck surgery or ir- radiation, but also as primary idiopathic disorder, especially in advanced age (4- 6). Congenital cricopharyngeal achalasia is a rare condition of unknown etiology, which usually presents with dysphagia, nasopharyngeal reflux during feeding, salivation, and choking in neonates and infants. It may resolve spontaneously, however, in many of these children, si - milarly as in adults, botulinum toxin applications, dilatations or myotomy are needed to resolve the problem (5-9). An acquired form of cricopharynge- al achalasia in older children has been reported extremely rarely and main- ly in connection with neurological and muscular diseases, e.g. cerebral palsy, muscular dystrophy, mitochondrial en - cephalomyopathy, Arnold-Chiari mal - formation (10,11). We present a case of this rare con- dition in a pre-adolescent girl without neuromuscular disorders. Furthermore, the possibility that autoimmune mecha - nisms were involved in its development is discussed. Case report A 12-year-old girl presented with a four-year history of dysphagia. She had no congenital, anatomic or neurologic abnormalities, and had an insignificant past medical history. Her eating pat - tern before the appearance of dysphagia was normal. The patient presented with difficulty in swallowing solid food, sen- sation of food impaction, and nodding her head during deglutition. The family history was negative for gastrointestinal disorders, but her mother has documen - ted autoimmune thyroiditis. She appe- ared healthy and well-nourished (50th percentile by weight, BMI at the 40th percentile). The physical and neurologi - cal examinations were unremarkable as well as her routine laboratory tests. The esophagogastroscopy was performed under conscious sedation but was un- successful due to the inability to enter a normal pediatric size endoscope into the esophagus. Subsequently, a radiological contrast swallow study was performed and interpreted as normal. As a result, the patient was diagnosed and treated for psychogenic dysphagia. The patient’s continuous problems despite one-year-long psychological tre- atment prompted re-evaluation of her diagnosis. Esophagogastroduodenosco - py under general anesthesia revealed ste- nosis at the level of the UES with intact mucosa (Figure 1). The lumen was signi - ficantly narrowed and it was impossible to introduce normal pediatric endosco- pe into the esophagus. A small-diameter (5.9 mm) baby endoscope was used to pass the narrowing, and mucosal biopsy specimens were obtained. The esopha - geal, gastric and duodenal mucosa was macroscopically normal. Histopatholo - gic investigation of several biopsies ta- ken from the proximal, middle and distal parts of the esophagus showed only si- gns of mild reflux esophagitis (grade 1b), but ruled out pathologic conditions that could result in esophageal stenosis, e.g. eosinophilic esophagitis or intraluminal 30 Zdrav Vestn | januar – februar 2017 | Letnik 86 MetaboLne in horMonske Motnje Figure 1: esophagoscopy with a small-diameter »baby« endoscope. stenosis at the level of the upper esophageal sphincter with normal mucosa. tumor growth. The muscularis propria was not included  in  the biopsy sam- ples. Subsequent radiological contrast swallow study with lateral views revea- led narrowing of the cervical esophagus at the level of the UES and incomplete relaxation of the cricopharyngeal mu- scle during deglutition with prominent horizontal notch on the posterior wall, regarded as a typical characteristic of cricopharyngeal achalasia (Figure 2). In addition, esophageal peristaltic waves were disturbed. A subsequent revision of the first ra- diological contrast swallow study revea- led that stenosis was already present at that time, but unfortunately, the radiolo - gist failed to pay attention to the signs of cricopharyngeal achalasia due to its ra- rity in pre-adolescents. The investigation was therefore misinterpreted as normal. The patient underwent dilatation with a Savary dilator (largest Ch42) under ge- neral anesthesia. Immediately following dilatation, symptoms of food impaction at the level of upper esophagus almost completely resolved. As it was impossible to perform esophageal manometric study before dilatation, we performed it few weeks after. The study demonstrated impaired relaxation of the UES. In addition, seve- rely disturbed esophageal peristalsis was noted, however, achalasia of the lower esophageal sphincter (LES) was ruled out by normal manometric findings of this region. During the diagnostic process, the patient was referred to an endocrino- logist to rule out the Allgrove syndro - me, characterized by achalasia of LES, alacrimia and adrenal insufficiency. Glucocorticoid levels were normal, however, elevated TSH with normal free T4 and T3 were found. Clinically and on ultrasonography enlarged thyroid gland was estimated with ultrasonographical - ly homogeneous structure.  Additional investigations revealed elevated levels of thyroid autoantibodies (anti-Tg 141 kE/l, anti-TPO >1300 kE/l), the diagno - stic hallmarks of Hashimoto’s thyroidi - tis. A few months later, the patient star - ted complaining about symptoms of dry eyes, prompting a suspicion for Sjögren’s syndrome. Despite the diagnosis of dry eye syndrome made by an ophthalmolo- gic examination, the diagnostic criteria for Sjögren’s syndrome were not met. Positive ANA titers (1:320) were present, however, autoantibodies for extractable nuclear antigens (ENAs) were negative. In addition, a mild vitiligo localized to the upper extremities was diagnosed in the follow-up period. The immunological work-up inclu- ding IgA, IgM, and IgG values, lympho- cyte subpopulations, classical, alternative and lectin pathways of complement acti - Cricopharyngeal achalasia in connection with autoimmune disorders in a pre-adolescent patient: a case report 31 kLinični PriMer Figure 2: r adiological contrast swallow study. the posterior protrusion at the level of the cricopharyngeus present during deglutition. vation, and tetanus and diphtheria anti- toxin titers were all normal. Based on these investigations, which revealed additional autoimmune disor- ders (Hashimoto’s thyroiditis, vitiligo, positive ANA), we suggest that cricopha- ryngeal achalasia may have an autoim- mune origin. During the follow-up over approximately one and a half years, the patient is reporting only occasional mild dysphagia for solid food and has no need for any further therapeutic procedures so far. Discussion Cricopharyngeal muscle is the main muscular structure of the UES. During the act of swallowing, tonic motor acti - vity in the cricopharyngeus is abolished and relaxation of the sphincter occurs. When UES relaxation is incomplete or uncoordinated with respect to pharyn- geal activity, the bolus is mishandled and repeated swallows are necessary to force the bolus into the upper esophagus (1,3). Various etiologies cause cricopha - ryngeal dysfunction with dysphagia, e.g. central or peripheral neurologic disor - ders, muscular disorders, previous neck surgery, irradiation, and old age  (5,7). Primary idiopathic cricopharyngeal dysfunction is a recognized entity in middle-aged and elderly patients, but is extremely rare in the pediatric popula- tion (3,7). The pathophysiology of the incom - plete relaxation of the cricopharyngeus is not fully understood. Many theori- es have been proposed to explain the relationship between cricopharyngeal dysfunction and dysphagia. Moreover, the variability in the appearance of the cricopharyngeus and the variety of as- sociated conditions makes a uniform pathophysiological explanation very un - likely. The most widely held theory rea- sons that the cricopharyngeus, which is normally in a state of tonic contraction, fails to relax to allow the passage of the food bolus into the esophagus. This the- ory has been supported by radiographic and manometric data. The work-up should include upper gastrointestinal endoscopy and radi- ological contrast swallow studies. En- doscopy may show a narrowing at the level of the UES and may be helpful to rule out other organic causes (tumors, reflux esophagitis, eosinophilic esopha - gitis with stenosis). Radiographically, cricopharyngeal achalasia is characteri- zed by a horizontal indentation on the posterior esophageal wall, with the con - trast passing the muscle very slowly and the cricopharyngeal muscle appearing to relax poorly (1,3,7,8). Esophageal ma - nometry may be useful and can provide information on the resting tone and re- laxation of the UES (2,3,7,8). Several treatment modalities are avai- lable, such as dilatation, local infiltration with botulinum toxin, and surgical myo- 32 Zdrav Vestn | januar – februar 2017 | Letnik 86 MetaboLne in horMonske Motnje tomy of the muscle, performed either endoscopically with laser or through an open transcervical approach  (5,8). The long-term success of dilatation as a tre- atment for cricopharyngeal achalasia has been detailed in several reports  (4,7,9). In many patients, especially those with mild symptoms, an initial trial of dila- tation is probably warranted and surge- ry should be reserved for those who do not respond to dilatation. Our patient underwent dilatation and had almost no residual symptoms at the level of the upper esophagus. Compared to cricopharyngeal acha- lasia, achalasia of LES is more common in the pediatric and adult population. A study that compared the prevalence of autoimmune disease in patients with esophageal achalasia to the general po- pulation revealed that patients with achalasia were 3.6-times more likely to suffer from any autoimmune conditi- on (Hashimoto’s thyroiditis, Sjögren’s syndrome, type 1 diabetes mellitus, SLE, etc.) (12). Our patient has been diagno - sed with cricopharyngeal achalasia, esophageal body motor dysfunction as well as a few autoimmune related con- ditions. These findings led us to presume that cricopharyngeal achalasia’s etiology might also have an autoimmune compo- nent, similar to achalasia of LES. Conclusion Cricopharyngeal achalasia is an extre- mely rare yet possible cause of dysphagia in the pediatric population. After exclu- sion of other frequent causes of dyspha - gia, a combination of esophagogastro - duodenoscopy, radiological contrast swallow study, and esophageal manome - try can help to confirm the diagnosis. An initial trial of dilatation appears to be a safe and effective option in the mana - gement of cricopharyngeal achalasia in children and surgery should be reserved for those who do not respond to dilata- tion. Our case report revealed that cri- copharyngeal achalasia may occur in as- sociation with some other autoimmune conditions, and that there is a possibility that autoimmunity may also play a role in pathophysiology of cricopharyngeal achalasia itself. To prove this hypothesis, it would be necessary to do additional studies. Conflict of interest statement Authors U. Vucina, P. Kotnik and R. Orel declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. References 1. Rosen R, Nurko S. Other Motor Disorders. In: Walker WA, Goulet O, Kleinman RE, Sanderson IR, Sherman PH, Shneider BL. 4th ed. Ontario, Canada: BC Decker; 2004. p. 424. 2. Staiano A, Cucchiara S, De Vizia B, Andreotti MR, Auricchio S. Disorders of upper esophageal sphincter motility in children. J Pediatr Gastroen - terol Nutr. 1987;6(6):892–8. 3. De Caluwe D, Nassogne MC, Reding R, de Ville de Goyet J, Clapuyt P , Otte JB. Cricopharyngeal acha- lasia: case reports and review of the literature. Eur J Pediatr Surg. 1999;9(2):109–12. 4. Skinner MA, Shorter NA. Primary neonatal cri- copharyngeal achalasia: a case report and review of the literature. J Pediatr Surg. 1992;27(12):1509–11. 5. Lawson G, Remacle M. Endoscopic cricopha- ryngeal myotomy: indications and technique. Curr Opin Otolaryngol Head Neck Surg. 2006;14(6):437–41. 6. Nelson JB, Richter JE. Upper esophageal mo- tility disorders. Gastroenterol Clin North Am. 1989;18(2):195–222. 7. Dinari G, Danziger Y, Mimouni M, Rosenbach Y, Zahavi I, Grunebaum M. Cricopharyngeal dys- function in childhood: treatment by dilatations. J Pediatr Gastroenterol Nutr. 1987;6(2):212–6. 8. Barnes MA, Ho AS, Malhotra PS, Koltai PJ, Mes- sner A. The use of botulinum toxin for pediatric cricopharyngeal achalasia. Int J Pediatr Otorhino- laryngol. 2011;75(9):1210–4. Cricopharyngeal achalasia in connection with autoimmune disorders in a pre-adolescent patient: a case report 33 kLinični PriMer 9. Lernau OZ, Sherzer E, Mogle P , Nissan S. Congeni- tal cricopharyngeal achalasia treatment by dilata- tions. J Pediatr Surg. 1984;19(2):202–3. 10. Scholes MA, McEvoy T, Mousa H, Wiet GJ. Cri- copharyngeal achalasia in children: botulinum toxin injection as a tool for diagnosis and treat- ment. Laryngoscope. 2014;124(6):1475–80. 11. Watanabe T, Shimizu T, Takahashi M, Sato K, Ohno M, Fuchimoto Y, et al. Cricopharyngeal achalasia treated with myectomy and post-ope- rative high-resolution manometry. Int J Pediatr Otorhinolaryngol. 2014;78(7):1182–5. 12. Booy JD, Takata J, Tomlinson G, Urbach DR. The prevalence of autoimmune disease in pati- ents with esophageal achalasia. Dis Esophagus. 2012;25(3):209–13.