Achalasia, Familial Esophageal

Description

Achalasia is a primary motor disorder of the esophagus. It is characterized by aperistalsis and a failure of the lower esophageal sphincter to relax due to a loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Patients typically present with dysphagia, regurgitation, retrosternal pain, and substantial weight loss (Farrokhi and Vaezi, 2007; summary by Gockel et al., 2010).

Clinical Features

Thibert et al. (1965) described 2 families, each with 2 affected sibs under 16 years of age.

Cloud et al. (1966) observed the disorder in 4 Apache Indian sibs less than 6 years old. Westley et al. (1975) reported 6 cases of achalasia, with symptoms beginning in infancy, in 3 sibships of an Apache Indian kindred.

Koivukangas et al. (1973) found Sjogren syndrome and achalasia in 2 sisters. (The Sjogren syndrome present in this family consisted of the triad of keratoconjunctivitis sicca, xerostomia, and rheumatoid arthritis or other connective tissue disease.)

Vaughan and Williams (1973) described 2 brothers, aged 2 and 8 years, with achalasia. Both presented with pulmonary complications caused by their achalasia. These brothers may have had the syndrome of glucocorticoid deficiency and achalasia (231550) because in the 8-year-old 'the clinical picture was obscured by the fact that the patient was hyperpigmented and had low plasma steroids.' In any case of achalasia in a child, especially if the disorder is familial (and especially if surgery is contemplated), adrenal insufficiency should be considered.

Inheritance

Dayalan et al. (1972) reported 3 documented and 4 probable cases of achalasia among a sibship of 8. The parents were of an uncle-niece consanguineous marriage.

Frieling et al. (1988) described 4 families with multiple cases. Their exhaustive review of the literature found about 5 times as many instances of affected sibs than instances of affected parent/child. There were 3 instances of affected twins; 1 pair was definitely monozygotic and 1 pair was dizygotic, being of unlike sex.

In a study of 1,012 first-degree relatives of 167 patients with achalasia, Mayberry and Atkinson (1989) were unable to detect a single established case of achalasia and none of the 447 sibs of patients with achalasia had the disease, although several had esophageal symptoms. They were able to find a report of only 1 instance of achalasia in monozygotic twins (Stein and Knauer, 1982). Kaar et al. (1991) reported affected brothers.

In a review, Gockel et al. (2010) stated that the inheritance pattern in the majority of cases of isolated achalasia is multifactorial. They also stated that a rare subform of early-onset achalasia probably exists, which is inherited in an autosomal recessive manner.

Molecular Genetics

See 163731.0002 for discussion of a possible association between variation in the NOS1 gene and achalasia.