Allgrove syndrome (3A) was first described in 1978. Allgrove et al (1) described 2 unrelated pairs of siblings with isolated glucocorticoid failure and achalasia. Three of these individuals also had defective tear production, leading the authors to speculate that the combination of achalasia, adrenal insufficiency, and alacrimia represented an inherited familial disorder. In the years following, a number of authors published similar reports that have helped to define the primary and associated features of this syndrome (2). Allgrove syndrome, or triple A syndrome (3A), is a rare autosomal recessive genetic disorder (Online Mendelian Inheritance in Man # 231550) characterized by the association of adrenal insufficiency (hereditary adrenal unresponsiveness to adrenocorticotropic hormone [ACTH]), alacrimia (absence of tear secretion), and achalasia of the cardia. In general, it is expressed in the first decade of life. Mutations in the achalasia, adrenocortical insufficiency, alacrimia (Allgrove) (AAAS) gene on chromosome 12q13 are responsible for the disorder. AAAS encodes a protein called ALADIN, which belongs to the family of WD-repeat-containing proteins and has been shown to localize to nuclear pore complexes (3–5).
Variable clinical presentations and outcomes for 3A have been reported; diagnosis may be late and may even be made in adulthood (6–10). Achalasia may also have a variable presentation: dysphagia may be present for years before the diagnosis of achalasia is made and may present as gastroesophageal reflux (11). When present, clinical digestive signs (achalasia) appear rapidly, and are severe: 11 patients required ≥1 surgical procedures (Heller operation) (10).
Up to the present time, 3A has been reported mainly in case reports and there are few series (12,13). Moreover, there is no study reporting manometric data in detail and assessing outcomes of 3A. The aim of the present study was to describe clinical and esophageal manometric characteristics and outcome in 3A in comparison with a group of children presenting with idiopathic achalasia (IA).
PATIENTS AND METHODS
This retrospective multicenter study recorded all of the patients with 3A from 3 tertiary pediatric gastrointestinal centers in France and Belgium. Children were followed up at Jeanne de Flandre Hospital, Lille, France, Trousseau Hospital, Paris, France, and Queen Fabiola Children's Hospital, Brussels, Belgium.
Achalasia on esophageal manometry was defined by insufficient relaxation of the lower esophageal sphincter (LES). Nine children fulfilling the inclusion criteria of achalasia and presenting with 3A (positive Schirmer test, achalasia, and adrenal insufficiency [Table 1]) were included in the study. They were compared with 9 children presenting with IA (Schirmer test negative and ACTH level within normal range). Each patient with 3A was paired for age (±1 year) at the time of the first manometry with a child with IA.
We retrospectively analyzed medical records, initial clinical signs and symptoms, initial ACTH data, genetic data, pH metry, barium meal, and esophagogastroduodenoscopy (EGD) data. Esophageal manometric parameters also were analyzed at diagnosis and on follow-up based on medical and surgical treatments performed. Success of treatment was classified as total, partial, or failure. Total success was defined as disappearance of all digestive and respiratory symptoms and normal growth. Partial success was defined as an improvement of digestive symptoms with incomplete recovery of clinical status. Failure was defined as no clinical improvement.
Esophageal manometry was performed using 4 water-perfused catheters. A low-compliance perfusion system and constant flow was maintained by an Andorfer pump. The 4 transducers were connected to both the infusion and the amplifier. The pressure signal was digitized with the Alpine Biomed GastroTrac System (Fountain Valley, CA). The manometric assembly was introduced transnasally without premedication and after fasting for 12 hours, and measurement of pressure, relaxation of the LES, and analysis of the esophageal peristaltic wave were performed. For this study, the following manometric normal ranges were used. For the LES pressure, normal range was 22.4 ± 4.7 mmHg and a decrease of at least 85% of the pressure during relaxation; normal esophagus body pressure was from 5 to 8 mmHg during swallowing; the amplitude of the peristaltic waves was 72 ± 17.2 mmHg, with primary peristaltic waves normally propagated as monophasic and nonrepetitive and always followed by LES relaxation. The normal upper esophageal sphincter (UES) resting pressure was between 40 and 100 mmHg. Achalasia was considered to be present when relaxation of the LES was insufficient (<85%) or absent (14). All of the manometric data were reviewed blind by 3 experts from the French-speaking Group of Pediatric Gastroenterology, Hepatology, and Nutrition (M.D.L., J.M.G., M.S.).
Nonparametric tests were used for statistical analysis. Data from 3A and IA and within the group of 3A before and after treatment were compared using a chi-square test. P < 0.05 was considered significant.
The 9 children (5 girls and 4 boys) with 3A were ages 2 to 11 years (mean age 7.1 years) at diagnosis of achalasia. Alacrimia evolving since birth was found in 6 children; in the other 3 children alacrimia appeared later. Seven children had adrenal insufficiency, and in the other 2, adrenal insufficiency appeared later. Six of these children also had autonomic dysfunction. The duration of follow-up ranged from 3 to 15 years (mean 8 years).
The 9 children (4 girls and 5 boys) with IA were ages 2 to 16 years (mean age 8.3 years) at diagnosis of achalasia, and all of them presented with normal adrenal function and normal Schirmer test. The duration of follow-up ranged from 2 to 12 years (mean 6 years).
All but 1 patient presented with clinical symptoms at the time of diagnosis: one 3A patient was completely asymptomatic but had adrenal insufficiency, alacrimia, and typical achalasia profile at manometry performed because of family screening for 3A syndrome. The most frequent symptoms at diagnosis of the 3A patients were dysphagia of liquids or solids (Table 1). Weight loss was common in the 2 groups (n = 5 in the 3A group, n = 4 in the IA group), whereas respiratory symptoms (pneumonia, chronic cough) were less frequent (n = 2 in the 3A group; n = 1 in the IA group). Genetic data were available for 5 of the 3A patients and showed mutations of the AAAS gene (Table 1).
An upper EGD was performed in 6 patients with 3A, showing esophageal dilatation or esophageal secretion stasis in 3 (Table 1). One 3A patient presented with gastroesophageal reflux at pH metry. Barium meal performed in 7 patients with 3A showed characteristic abnormalities involving bird's beak deformity and a dilatation of the body of the esophagus and delayed evacuation of the contrast in 4 of 7 patients (Table 1).
Esophageal manometry was performed in all of the patients with 3A (Table 1), showing abnormal relaxation of the LES in all. UES pressure was normal in 7 and hypotonic in 2, LES pressure was hypertonic in 3 and normotonic in 6, whereas the peristaltic wave showed lack of propagation in 8 with abnormal amplitude in 7 of 8.
All but 1 patient (the 3A patient mentioned above who was completely asymptomatic) received nifedipine and/or esophageal dilation and/or surgery (Table 2). Patients with 3A presented a more severe evolution than those with IA, treatment of only 2 of the 3A patients being considered a total success compared with 7 total successes in the IA group, independent of the treatment (P < 0.03). Seven 3A patients received a Heller myotomy associated with a Nissen fundoplication, whereas 5 IA patients were operated on using the Heller procedure. Among the seven 3A patients who were operated on by the Heller procedure, we examined pre- and postoperative manometric features to establish prognostic factors for success or failure of treatment. Preoperative LES hypertonia was found in three 3A patients who were treated with surgery and did not predict outcome after treatment (P = 0.53). Although not significant (P = 0.28), the two 3A patients with high amplitude waves preoperatively (with signs of struggle and the presence of repetitive polyphasic waves) failed to improve after surgery.
Six of the 3A patients presented with dysautonomy; 1 responded well to treatment with nifedipine and 2 failed after surgery, whereas the other 3 showed partial success after surgery.
3A is a rare disease with an unknown annual incidence, and IA is a rare disease with an annual incidence of approximately 1/100,000 (15). In our study, only 9 patients were included from 3 tertiary pediatric gastrointestinal centers in France and Belgium. Despite the low number of patients, we could precisely describe their clinical characteristics and manometric features (each patient had at least 2 manometric examinations that were reviewed by an expert panel) as well as their outcomes, and we compared these with those of patients with IA. Our series is the first to report clinical and manometric data and outcome of 3A in comparison with IA. It shows that the clinical presentation of 3A and IA was not different, with the exception that asymptomatic patients were seen only in the 3A group. Indeed, 3 patients with 3A had no digestive signs at the time of diagnosis because 3A was suspected because of alacrimia or adrenal insufficiency or was detected during a family screening (1 patient was indeed completely asymptomatic). The 3A patients underwent at least EGD (n = 6) or barium meal (n = 7) or both (n = 5); esophageal manometry was performed in all 3A patients including those with no signs (family screening). All manometric data were blindly reviewed by 3 experts from the Group of Pediatric Gastroenterology, Hepatology, and Nutrition. We can therefore confirm that they had achalasia and not another condition. Despite this, we were not able to demonstrate any difference in the first manometric profile in 3A compared with IA.
The definition of achalasia in children is different from that in adults. In adults, IA is characterized by esophageal aperistalsis and abnormal LES relaxation in response to deglutition (16–19). In children, absent LES relaxation is universal but aperistaltism is rare and is replaced by a dyskinetic esophagus, as already shown by Viola et al (20). Esophageal manometry has been used widely in the diagnosis of esophageal achalasia because of its simple procedure and high accuracy (21). All patients with 3A underwent esophageal manometry, although not all had EGD or a barium meal. The pressure curve is accurate and sensitive in detecting the baseline pressure of different parts of the upper digestive tract and its changes during swallowing. The pressure could be a good indicator for the severity of the disease, for selection of proper treatment, and for evaluation of treatment results. The high LES pressure noted in patients with 3A is suggestive of a peculiar pattern in 3A affecting the LES and the lower part of the esophagus. New high-resolution manometry techniques should help to define more precisely the manometric profile and outcome of children presenting with 3A (22).
In the treatment of achalasia, reduction in the LES pressure is the primary objective, but there is no consensus among medical treatment (nifedipine), dilation, botulinum toxin injection, or surgery about the type of treatment to use as the first line. Our small series reflects this lack of standardization, but confirmed the high rate of surgical treatment in 3A. Heller esophagocardiomyotomy was invented in 1913, and was popularized by Zaaijer around 1923 (23). The treatment has a high degree of safety, is effective, and has a long effective duration in adults (24–26). Although the “classic” Heller myotomy was used in all surgically treated patients with 3A (and IA), the operations were performed by different surgical teams in the 3 different centers, which could influence the surgical outcome.
We recognize that there are several significant limitations to this small retrospective study that reduce the impact of our findings. With regard to study design, there was no standardized evaluation of symptoms and investigation and no systematic follow-up. In addition, this study spans a long period during which multiple surgeons and endoscopists used a variety of treatment protocols as the management of this disease evolved. Given these limitations and the rarity of achalasia in children, our study is not adequately powered to make a conclusion regarding the efficacy of the different treatments used; however, our results show that both in 3A and IA, pneumatic dilation often failed, as did nifedipine treatment. Most of the patients eventually underwent Heller myotomy, but this often failed in patients with 3A. Whatever the treatment modalities, our study clearly shows that failure is more frequent in 3A, confirming that 3A has a more severe outcome than IA.
We could not demonstrate any prognostic value of preoperative or postoperative manometry features in patients with 3A; however, whether preoperative LES hypertonia or high-amplitude waves (that were associated with treatment failure in 3 of the patients with 3A) could be predictive of treatment failure remains to be studied.
Patients with 3A have more severe evolution than those with IA, despite presymptomatic diagnosis in cases of family screening. Families and doctors should be informed about the high rate of treatment failure in 3A. Despite these restrictions on our results, we believe that this series contributes additional data on a rare condition for which the therapy is continually progressing.
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