Analysis of a set of patients undergoing Nissen fundoplication

Background: Cornelia de Lange syndrome (CdLS) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth problems and development delay. The high clinical and genetic variability the existence of a CdLS Spectrum has been recently suggested 1

Up to 80% of CdLS patients are assumed to have symptoms of gastroesophageal reflux disease (GERD) which may become apparent in a highly variable manner 2 3. The aim of this study is to retrospectively describe a set of 23 CdLS patients who underwent Nissen Fundoplication (NF) for GERD, correlating with clinical and genetic features. Few data are present in Literature 4. Moreover in this study we would like to find possible predictive factors for surgical treatment for GERD.


Data were collected retrospectively in all CdLS patients undergoing NF for GERD.


Mean age of patients was 9.5 years; mean age of surgical treatment was 4 years. There were 13 females and 10 males. 21/23 (91.3%) of our patients had a molecular characterization, while 2/23 (8.6 %) had a clinical diagnosis according the new criteria1. In patients with a known molecular defect, 21/21 (100%) showed an NIPBL gene mutation, truncating in 12/21 (52.2%).
Patients presented predominantly underweight with a BMI less than 10th centile in 14/23 (60.9%). Regarding intellectual disability 5, most patients have a severe-profound intellectual disability (13/23, 56.5%), while 7/23 (30.4%)  were moderate and only 3 patients had a borderline mild development (13%). Upper limb malformations were evident in 10/23 (44%).

21/23 (91%) patients that underwent NF had previously performed an extended ineffective drug treatment with protein pump inhibitors (PPI). The great majority of our patients presented with atypical behavioural symptoms not controlled by medical therapy.

Endoscopy revealed pathological findings in 14 cases (9 esophagitis, 4 hiatal hernia, 1 Barrett’s esophagus). Most of the patients (18/23; 78%) underwent isolated intervention of NF. In 2 patients it was performed during surgical correction of diaphragmatic hernia and in 3 patients there was direct NF in conjunction with placement of gastrostomy tube.
For 21/23 (91.5%) patients, clinical follow-up showed good results while in 2/23 (8.5%) a second surgical intervention was necessary. The major medical complication after NF was dumping syndrome observed in 4/23 patients (17%); this situation resolved within 1 year. 


We have described our set of patients undergoing NF. We highlight that all tested patients have an NIPBL mutation, frequently  associated with a more severe clinical phenotype. Accordingly, most of our patients presented with severe-profound Intellectual Disability and a poor weight gain. Clinical GERD symptoms are often irritability, hyperactivity and behavioral changes with self-harm. Endoscopic findings in patients who underwent NF included esophagitis, PPI not responsive in most patients. 


Our data demonstrate that severe GERD, not responsive to PPI treatment, is mostly evident in classical CdLS spectrum patients. Upper limb malformation and early severe psychomotor delay are clinical markers of a potential severe GERD. So in these subjects it is mandatory to carefully monitor the effectiveness  of medical treatment of GERD and  to consider surgical treatment as a concrete option. With persistent behavioral symptoms despite PPI therapy, an endoscopy is mandatory to exclude an esophagitis PPI non-responder, particularly in patients with NIPBL mutations or severe phenotypes.

  1. ^ Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tümer Z, Van Balkom IDC, Hennekam RC. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nat Rev Genet. Oct;19(10):649-666. (2018)
  2. ^ Kline, A. D. et al. Natural history of aging in Cornelia de Lange syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 145C, 248–260 (2007). 
  3. ^ Luzzani, S., Macchini, F., Valade, A., Milani, D. & Selicorni, A. Gastroesophageal reflux and Cornelia de Lange syndrome: typical and atypical symptoms. Am. J. Med. Genet. 119A, 283–287 (2003)
  4. ^ Szyca R, Leksowski K. Cornelia de Lange syndrome - characteristics and laparoscopic treatment modalities of reflux based on own material. Wideochir Inne Tech Maloinwazyjne. Sep;6(3):173-7. (2011)
  5. ^ Cereda, A. et al. A new prognostic index of severity of intellectual disabilities in Cornelia de Lange syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 172, 179–189 (2016).
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Presenting Author: Barbara Parma

Authors: Barbara Parma 1, Paola Cianci 2, Valentina Decimi 3, Milena Mariani 1-8, Roberto Panceri 4,A Cereda 5,  Maurizio Cheli 6, Pietro Betalli 6, Roberta  Onesimo 7 , Giuseppe Zampino 7 and Angelo Selicorni 1

Conflicts of Interest: None

1 Department of Pediatrics, ASST-Lariana. Sant’Anna Hospital, San Fermo della Battaglia (Como), Italy.
2 Department of Clinical and Experimental Medicine, Ospedale Pediatrico Filippo del Ponte, Varese, Italy.
3 Department of  Pediatrics, University of Milan Bicocca, Monza Italy.
4 Department of Pediatrics, Fondazione MBBM, Ospedale San Gerardo, Monza Italy.
5 Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo. Italy.
6 Pediatric Surgery Unit, ASST Papa Giovanni XXIII, Bergamo. Italy.
7 Center for Rare Diseases and Birth Defects Department of Woman and Child Health, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy.
8 Clinical Paediatric Genetic, University of Milan Bicocca, Milan, Italy.

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Modificado por Gerritjan Koekkoek em 2023/03/29 15:42
Criado por Gerritjan Koekkoek em 2019/07/09 15:46

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