Introduction

Achalasia is a primary esophageal motility disorder characterized by esophageal aperistalsis and failure of the lower esophageal sphincter (LES) to relax with swallowing, secondary to a degeneration of the myenteric plexus [1, 2]. Its etiology remains, to date, unknown. However, the existence of family cases—most often falling under Allgrove syndrome—suggests the existence of genetic factors predisposing to this condition [3, 4]. The genetic etiology of achalasia is suggested by the familial occurrence where several members of the same family can be affected [5, 6]. Achalasia is rare in children. In most cases, it is idiopathic with no family history. It occurs exceptionally in siblings. To our knowledge, only 33 cases of familial childhood achalasia were collected in the literature till 1987. Familial achalasia (FA) is a very rare condition [7]. Very few studies are available and tackle usually isolated cases [8]. Its management has not been established: pneumatic dilation (PD) or Heller’s cardiomyotomy. This work aims to evaluate the prevalence of FA, study its clinical profile in a large series and assess the efficacy and safety of PD in this context.

Materials and methods

In this prospective study, 817 patients with achalasia were enrolled over a period of 20 years (1990–2010), 425 were females (F), 392 were males (M), mean age: 38.3 years ± 18.7 years (3 months–86 years), children presented 8% of cases. Achalasia was diagnosed on clinical, endoscopic, radiological and manometric arguments. All patients underwent a standardized symptoms questionnaire, an upper endoscopy, a barium esophagogram and esophageal manometry. Achalasia definitive diagnosis was made according to manometric criteria: a total aperistaltisis associated or not to an increased LES tone (> 34 mmHg) and/or a LES failure to relax (< 80% of the basal pressure). FA isolated or associated to Allgrove syndrome was systematically checked in both parents and siblings. Its diagnosis was established when at least two members of one family had achalasia, whether it was isolated (sporadic achalasia) or fallen under Allgrove syndrome (syndromic achalasia). Allgrove syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency and neurological abnormalities. Rarely reported in adult patients, it is usually present during the first decade of life. Recent studies have identified mutations in the triple A syndrome gene (AAAS), a candidate gene on chromosome 12q13 (16 exons). The most common mutations are missenses or frameshift, predicting a truncated presumably non-functional protein called Alacrima Achalasia aDrenal insufficiency Neurologic disorder (ALADIN). The IVS14 and EVS9 are the most common mutations. Its diagnosis was made when at least two out of the 3 following signs were present: alacrima, achalasia, adrenal insufficiency. It was classified as 2A in case of absence of adrenal insufficiency, 3A when the 3 signs were present and 4A in case of their association with neurological abnormalities.

Graded PD with Witzel dilator and/or Rigiflex balloon was performed for all patients. It was carried out every week until remission. After complete dilation, the patients were controlled after 1 month, 6 months and then yearly. Clinical results were evaluated according to Vantrappen classification and/or Eckardt score. If during the follow up symptoms relapsed, patients underwent subsequent sessions of PD (1 session to 3 sessions yearly) or Heller’s cardiomyotomy.

Results

Discussion

FA is a very rare disease [7]. Its prevalence is unknown, and only scattered family and case reports exist in the literature [9]. This prospective work focused on a large series of 41 patients with FA among the 817 patients with achalasia included in our study. These patients came from the 48 provinces of Algeria as our department is a reference center for managing this condition. This is a homogenous and representative sample of Algerian population, from which it was possible to estimate, for a period of 20 years, the relative prevalence of this disease to the whole cases of achalasia in Algeria and to study its clinical and para clinical features. Our work has shown that its relative prevalence was estimated to be 0.05 (5 cases of FA/100 cases of achalasia) CI 95%: (0.035, 0.065). FA is more frequent in children, Zimmerman and Rosensweig [10] have commented that approximately two thirds of reported cases of FA have occurred in children under the age of 15 years, which is similar to our result (n = 31, 75% of cases). There is a preponderance of horizontal transmission in FA [11]. It suggests a genetic predisposition that is transmitted as an autosomal recessive trait [8]. Westley and colleagues [12] believed that the lack of evidence of vertical transmission and the occurrence of achalasia in children of both sexes and in multiple members of an extended family constituted strong evidence that a recessive gene was responsible for infantile achalasia [9]. Thus, vertical transmission may well exist, but its documentation is difficult (Table 1) [11].

Allgrove syndrome is a very rare genetic autosomal recessive disorder. Its occurrence is favored by consanguineous marriages. The AAAS gene responsible for this disease is carried by the long arm of chromosome 12 (12q13) and contains 16 exons. Mutations of this gene that were currently implicated are IVS14, the most common mutation, and EVS9 [18–19]. Alacrima was constant and present at birth in all cases of Allgrove syndrome this should lead to the diagnosis. Achalasia is the most common disorder seen after alacryma. Adrenal insufficiency is not constant and neurological abnormalities can exist without it [20].

Despite its rarity, Allgrove syndrome must be known by the internist who may have to make the diagnosis in an adult patient suffering from asthenia, melanoderma, and adrenal insufficiency or a predominantly motor peripheral axonal neuropathy which may first suggest Charcot-Marie-Tooth disease or a motor neuron disease. The importance of its multidisciplinary management is certain, as the diffusion of its knowledge in the medical community, because of its prognosis which is hampered by neuropathic and adrenal damage.

In our study, two groups of FA were identified. Group A: IFA in 3 families (n: 7, F: 4, M: 3; mean age: 14.6 ± 8). Group B: AFA in 15 families (n: 34, F: 20, M: 14; mean age: 16.8 ± 8). These results show a high rate of AFA. This is most probably related to the widespread tradition of consanguineous marriage in Algeria. Reports of IFA are very rare and represent less than 1% of all patients with achalasia [21]. So far, no study has compared AFA and IFA. Based on reported cases and our results, we can notice the differences summarised in (Table 2). Most of our FA patients were children. This explains the low long-term success of PD dilation because it is characterized as a temporizing, non-definitive procedure for this age [9, 22], and surgical management may be the best initial approach [7, 9].