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Home , Enteropathy, Sandifer syndrome

Acta Pediatrica Mediterranea, 2007, 23: 153

SANDIFER SYNDROME AND THE HERBSTTRIAD. AN UNUSUAL PRESENTATION OF GASTRO- ESOFAGEALREFLUX

MARTA MATTIUZZO - MARISA CALACOCI - LISA PECORARI - ANTONELLA SAVELLI - *ELISABETTA MARCHETTI - CATERINA BORGNA-PIGNATTI Clinica Pediatrica - Università degli Studi di Ferrara - *Dipartimento di Medicina Sperimentale e Diagnostica - Sezione di Anatomia Istologia e Citologia Patologica - Università degli Studi di Ferrara (Direttore: Prof.ssa Caterina Borgna-Pignatti)

[Sindrome di Sandifer e triade di Herbst. Un caso insolito di malattia da reflusso gastro-esofageo]

SUMMARY RIASSUNTO

The association of protein-losing , siderope- La presenza di enteropatia prot e i n o - d i s p e r dente, anemia nic anemia, finger clubbing (Herbst triad) and Sandifer syndro- si d e r openica, clubbing (triade di Herbst) e Sindrome di Sandifer me (reflux oesophagitis and head cocking) represents an unu- (esofagite da reflusso e torcicollo parossistico) costituisce un’in - sual manifestation of gastro-esophageal reflux disease solita manifestazione di malattia da reflusso gastro - e s o f a g e o (GERD). Herein we report a patient presenting this complex (GERD). Riportiamo di seguito il caso di un paziente con questo clinical picture and, in addition, allergic asthma and allergies to complesso quadro clinico e, inoltre, asma allergico e allergie a several foods. The surgical correction of the gastro-oesopha- diversi alimenti. La correzione chirur gica del reflusso gastroe s o - geal reflux resolved the reflux itself and related symptoms. fageo ha portato ad una risoluzione dello stesso e dei sintomi as s o c i a t i .

Key words: , Herbst triad, gastro - e s o p h a - Parole chiave: Sindrome di Sandifer, triade di Herbst, malattia geal reflux disease da reflusso gastro-esofageo

Introduction The association of GER with finger clubbing, sideropenic anaemia and hypoprotidemia is much Gastro-esophageal reflux is defined as the rarer and it is called Herbst triad: the first three backflow of gastric contents into the . To cases were described in 1976(3), and, subsequently, 2 a limited degree, its occurrence without associated further cases by Sacher( 9 ), in 1990. We report the symptoms is considered to be a physiological phe- case of a patient suffering from GER, Sandifer syn- nomenon. An increase in rate, quantity and duration drome, protein-losing enteropathy, persistent anae- is generally associated to symptoms and/or anato- mia and finger clubbing, whose GER and associa- mical lesions and this generates the condition of ted symptoms only regressed after surgical correc- gastro- (GERD); it can be pri- tion of the reflux. mary or secondary to various such as food allergy, metabolic disease, central nervouse system Clinical case abnormalities. GERD, in paediatric patients, is a condition The patient was an 8 years old boy, who had that usually responds to therapy with protonic pump epigastralgia and pyrosis, (mainly postprandial), inhibitors, while surgical correction is rarely requi- vomiting, sometimes several times a day, drooling, red. An unusual clinical presentation of GERD is rumination, head tilting, particularly after meals, the Sandifer syndrome, a combination of gastro- reduced growth, decreased appetite and playing oesophageal reflux disease with spastic a c t i v i t y. Before arriving to our department, the and dystonic body movements with or without hia- patient had undergone an esophagus-gastro-duode- tal (4). noscopy (EGDS), which had shown, macroscopi- 154 M. Mattiuzzo - M. Calacoci et Al cally, a bleeding esophageal mucosa and ulcerative The patient was given a high-protein and eli- lesions and mild . Histologically, at the mination diet in accordance with the results of esophageal level, we found an extensively ulcerated allergen-specific IgE, and was treated with omepra- mucosa, granulation tissue permeating the epite- zole 40 mg/daily, disodium chromoglycate 250 lium and cronic . mg/8 hr and iron at first i.v. and then per os. In addition, chronic first degree duodenitis After about two months of medical and dietary was demonstrated. The child was treated with cisa- treatments the child improved but hypoprotidemia pride 0,2 mg/Kg/every 8 hr and ranitidine 5 and iron deficiency anemia persisted with serum mg/Kg/every 12 hr and then with omeprazole 20 protein values ranging from 4,5 g/dl and 5,8 g/dl mg daily, with a partial improvement. and Hb from 5,9 g/dl and 9,3 g/dl. The esophageal 24 hours pH measurement A follow-up EGDS showed a total regression recorded a reflux index of 38%, 18 long-lasting of the ulcerative lesions and of inflammation in the reflux episodes (> 5 minutes) with the longest esophageal and gastric mucosa. Histologically reflux episode of 60 minutes; the second EGDS chronic with eosinophilic granulocyte was unchanged. The histology of the sample obtai- infiltration of the esophageal mucosa (59 hpf) and ned during the first colonoscopy, performed at cardias level (21 hpf) was present. The duodenal elsewhere, suggested the presence of IBD on the biopsy demonstrated regular villi and mild lympho- basis of moderate lympho-plasma cellular infiltra- plasmacellular infiltration of the tunica mucosa. tion of the tunica propria mucosa, where neutrophil Based on the histological findings and on the and nodular aggregation with occasional partial response to the therapy with protonic pump cryptitis were present. inhibitors, was suspected On admission, the patient, was in fair general and an elementary diet was suggested but his condition, he was pale, and the abdomen was tender parents refused. Hence oral prednisone at the dosa- to palpation in the epigastric area and in the lower ge of 1,5 mg/kg/day was started and omeprazole 40 quadrant. Finger clubbing was present. On admis- mg/daily were continued, but gastric discomfort sion he had a weight of 26.6 Kg (50th percentile) and lack of appetite worsened and therefore cortico- and a height of 129 cm (50th percentile). steroid therapy was discontinued. At this point, Laboratory tests showed Hb 8.9 g/dl MCV 74 fl, given the lack of response to the therapeutic trials, WBC 4700/mmc with hypereosinophilia (700/ml), the patient underwent a surgical procedure of reflux alfa-1-fecal antitrypsin 23 mg/dl, total serum pro- correction (Tupet funduplication). tein 4.5 g/dl, absence of proteinuria, serum iron 13 Five months later, all laboratory and clinical mcg/dl, ferritin < 5 ug/dl. The inflammation tests were normal and regression of finger clubbing indexes were within normal limits. Iron absorption was observed. Growth resumed to normal levels test was normal. with weight and height at the 75th percentile; Hb, Repeated stool searches for occult blood were MCV, serum iron, ferritin and serum proteins were positive in only two occasions. Stools were negati- normal, while the RAST remained abnormal for ve for viruses, parasites and bacteria. Intestinal per- some foods and modest hypereosinophilia meability test to lactulose/mannitol ratio was 0.067. (558/mmc) persisted. Three years after surgery, the Sweat test and ANCA were normal. Total IgE 2455 child is asymptomatic, he enjoys a free diet and UI/ml, allergen-specific IgE positive for many dif- shows a regular growth. All laboratory tests remain ferent kinds of food (peanut 66,2 KUA/L, cod 49,3 within the normal range. KUA/L, lobster 24,7 KUA/L, and mild positivity to many other foods), prick by prick positive for Discussion and conclusions celery. Intestinal scintigraphy with marked leucocy- tes and a upper gastrointestinal series with small- In our patient, the complex clinical picture bowel follow-through were normal. caused some diagnostic difficulties in diff e r e n t i a- The second colonoscopy did not allow a com- ting the condition from eosinophilic esophagitis and plete visualization of the colonic mucosa because of chronic inflammatory bowel disease (IBD). T h e poor intestinal toilet, but the stool free segment eosinophilic infiltration of the esophageal mucosa appeared to be normal. Microscopically, a mild and its partial response to therapy with omeprazole chronic limphoplasmacellular infiltration was docu- seemed to support the diagnosis of eosinophilic mented. esophagitis. Sandifer syndrome and the Herbst triad. An unusual presentation of gastro-esofageal reflux disease 155

This diagnosis must be taken into considera- References tion every time the symptoms suggesting a GER disease do not respond to therapy with protonic 1) Berant M, Khourie M and Manzies I Effect of iron on pump inhibitors, especially if the patient has a per- small intestinal permeability in infants and young chil - dren J Paediatr Gastroeneterol Nutr 1992; 14: 17-20, sonal or family history of allerg y. The histologic 2) Greenwald M, Couper R, Laxer R et al. G a s t ro - finding of an eosinophil count in the upper esopha- oesophageal reflux and esophagitis-associated hyper - geal mucosa higher than a 20 per hpf is diagnostic t rophic osteoart h ropathy J Ped Gastroenterol Nutr for eosinophilic esophagitis(7, 8, 10). The hypothesis 1996, 23: 178: 181. that all signs, symptoms and laboratory abnormali- 3) Herbst J, Johnson DG, Oliveros M A. Gastro-oesopha - geal reflux with protein-losing enteropathy and finger ties, presented by our patient, were due to gastro- clubbing Am J Dis Child 1976; 130: 1256-1259. esophageal reflux disease is supported by the com- 4) Lehwald N, Kraush M, Franke C, Assmann B, Adam R, plete resolution of symptoms only after a reflux Knoefel W T. Sandifer syndrome-a multidisciplinary surgical correction. This does not support a diagno- diagnostic and therapeutic challenge. Eur J Pediatr ( 1 0 ) Surg. 2007; 17 (3): 203-6. sis of eosinophilic esophagitis . Also, the patient 5) Lundstrom U, Perkkio M, Savilahti E et al. I ron defi - remains symptomless three years after surg e r y ciency anaemia with hypopro t e i n e m i a Arch Dis Child without any therapy. 1983; 58: 438-441. Gastro-esophageal reflux and esophagitis 6) Naiman JL, Oski FA, Daimond LK et al The gastrointe - could be associated with hypertrophic osteoarthro- stinal effects of iron deficiency anemia Pediatrics 1964; 33: 83-99. ( 2 ) p a t h y . The physiopathological mechanisms cau- 7) Noel R, et al. Eosinophilic Esophagitis NEJM 2004; sing finger clubbing are still incompletely under- 351: 940-941. stood. It can appear as an isolated sign or in asso- 8) Orenstein S, Shalaby T.M, Di Lorenzo C et al. T h e ciation with chronic proliferative periostitis and spectrum of pediatric eosinophilic oesophagitis beyond infancy: a clinical series of 30 children Am J synovitis, forming the clinical picture of hyper- Gastroenterol 2000; 95: 1422-1430. trophic osteoarthropathy. It is often associated with 9) Sacher P and Stauffer UG. The Herbst triad: report of a number of pulmonary, cardiac, gastrointestinal, two cases J of Pediatr Surgery 1990; 25: 1238-1239. infectious, endocrine, and multisystem diseases. 10) S. Anna AM, et al. J Paediatr Gastroeneterol Nutr 2004; Most microscopic and imaging studies of clubbed 39: 373-7. 11) Spicknall KE, Zirwas MJ, English III JC. Clubbing: An fingers reveal hypervascularization of the distal update on diagnosis, differential diagnosis, pathophy - digits. s i o l o g y, and clinical re l e v a n c e. J Am Acad Dermatol. Recent research shows that when platelet pre- 2005; 52: 1020-8. cursors fail to become fragmented into platelets within the pulmonary circulation, they are easily trapped in the peripheral vasculature, releasing pla- telet-derived growth factor and vascular endothelial growth factor, promoters of vascularity and, ultima- tely, clubbing(11). The long follow-up without symptoms and normalization of laboratory abnormalities in the absence of any pharmacological or dietary therapy suggests that in our patient a severe gastro-oesopha- ______geal reflux was responsible for the entire clinical Request reprints from: picture, including the protein-loss and anaemia. Prof.ssa CATERINABORGNA PIGNATTI Iron deficiency, in fact, appears to damage the Sezione di Pediatria ( 1 , 5 , 6 ) Università degli Studi di Ferrara jejunal mucosa causing hypoprotidemia and an Via Savonarola, 9 inability to absorb iron, starting a vicious circle that 44100 Ferrara leads to persistent anemia. (Italy)