Allgrove syndrome is a rare genetic disease manifested by alacrimia, achalasia and addisonism. The disease is caused by a mutation of AAAS, which is localized on the 12th chromosome, and is inherited in an autosomal recessive way. Pathology is characterized by “dry eye” syndrome, disorders of swallowing and promotion of food into the stomach, deficiency of glucocorticoids and neurological symptoms. To diagnose Allgrove syndrome, genetic testing, hormonal blood and urine tests, instrumental visualization of the adrenal glands, esophagus, and brain are prescribed. Treatment is symptomatic, taking into account the leading clinical manifestations.
E27.4 Other and specified insufficiency of the adrenal cortex
The characteristic triad of symptoms was first described in 1978 by the English pediatrician and endocrinologist J. Allgrove and later named after him. The genetic basis of the disease was revealed only after 18 years. Allgrove’s disease is also called the “three A” syndrome. In practical genetics, the prevalence of the disease is 1 case per 1 million population. Given the polymorphism of symptoms and the low alertness of doctors regarding this syndrome, in many cases it is diagnosed belatedly.
The etiological structure of Allgrove syndrome was finally deciphered in 1996. The disease develops due to a mutation in the AAAS gene. It is located on the long arm of chromosome 12 at the 12q13.13 locus. The gene consists of 16 exons and encodes more than 500 amino acids in the ALADIN protein, which has regulatory functions. This protein is expressed in large quantities in the adrenal glands, gastrointestinal tract and nervous tissue.
Pathology has an autosomal recessive inheritance pathway. The syndrome is observed in male and female newborns with the same probability if the parents are carriers of the mutant gene. The probability of recurrence of the disease during the next pregnancy is 25%. Family cases of pathology are mainly traced in residents of Africa and Asia, while isolated cases are recorded among Europeans.
The mechanism of the disease development is not thoroughly studied. Although scientists associate the multisystem nature of the lesion with pathologies of the ALADIN protein, no common damaging agent has yet been found for 3 typical target organs: esophagus, lacrimal glands and adrenal glands. The complexity of determining the pathogenesis is due to the variability of the phenotype in patients with Allgrove syndrome, since with the same mutation, the nature of the course varies from asymptomatic to extremely severe.
The first sign of Allgrove syndrome is alacrimia – a decrease or complete absence of tears, which is caused by hypoplasia of the lacrimal glands. It manifests itself in young children, in some cases parents notice an alarming symptom in infants 5-6 months old. Due to insufficient moistening of the eyes, older children complain of burning, pain, and a feeling of a foreign body. Often their vision decreases, recurrent keratitis occurs.
The second pathognomonic sign is achalasia of the cardia, which occurs in 75% of patients aged up to 15-16 years. Discoordination of the cardiac sphincter and violation of esophageal peristalsis is manifested by swallowing disorders. Patients choke and choke on food, may accidentally inhale food particles. Over time, functional obstruction of the lower third of the esophagus develops, which disrupts enteral nutrition.
Chronic adrenal insufficiency, which is part of the Allgrove syndrome triad, develops in the second to third decade of life. In some people, clinical manifestations of hormonal deficiency occur only in old age. Externally, the pathology is manifested by pigmentation of the skin and mucous membranes, which acquire a light bronze hue. There is a decrease in body weight, unmotivated weakness, low blood pressure.
The clinical triad is often supplemented by neurological symptoms. Allgrove syndrome is characterized by motor disorders caused by bulbospinal amyotrophy, motor sensory polyneuropathy, lower spastic paraparesis. Vegetative disorders occur: orthostatic hypotension, impaired pupillary reactions, decreased sweating and saliva production.
Adrenal insufficiency in the absence of treatment manifests itself as an addisonic crisis. Hypoglycemia, shock, and impaired consciousness develop. Alacrimia is complicated by keratopathy and progressive loss of vision. Neurological disorders cause mental retardation, dementia, and parkinsonism. Achalasia is accompanied by aspiration of food masses and pneumonia with a prolonged course. If you inhale a large portion of food, there is a risk of suffocation.
Allgrove syndrome is often accompanied by a complex of congenital anomalies of appearance. Children have an elongated face, sparse or missing eyelashes, a large distance from the nostrils to the edge of the upper lip. The defeat of the musculoskeletal system is manifested by scoliosis, osteoporosis, stunting. A serious threat is the long QT syndrome, which is associated with the risk of life-threatening arrhythmias.
The initial examination of patients is carried out by a pediatrician or therapist, depending on the timing of manifestation and the nature of symptoms. During physical examination, attention is drawn to redness and dryness of the eyes, “tanned” skin tone, typical facial anomalies. For the diagnosis of Allgrove syndrome, a complex of laboratory and instrumental studies is required, such as:
- Instrumental methods. Ultrasound of the adrenal glands is prescribed to visualize signs of atrophy and calcification of the organ, volumetric neoplasms. The presence of achalasia is confirmed by the data of X-ray examination of the esophagus with contrast, esophageal manometry. Neurosonography, CT or MRI of the brain allows to exclude the primary lesion of the nervous system.
- Schirmer’s test. The study is conducted for the objective diagnosis of lacrimation disorders. The intensity of the production of tear fluid is estimated by the length of the moistened piece of paper placed on the edge of the lower eyelid. Alacrimia is diagnosed with a wet spot length of less than 5 mm.
- DNA diagnostics. Detection of AAAS mutation is the only method of confirming the diagnosis, which is prescribed to all patients with suspected Allgrove syndrome. However, about 5% of patients have atypical mutations that cannot yet be identified by routine methods.
- Hormonal profile. Adrenal insufficiency is characterized by a decrease in the daily excretion of 17-CS and cortisol in the urine, an increase in the concentration of ACTH in the blood. Additionally, a stimulation test with ACTH, an insulin hypoglycemia test is performed.
- Consultations of specialists. Patients need to be examined by an ophthalmologist with biomicroscopy of the eye, visometry, fundus examination. Motor and intellectual disorders – indications for examination by a neurologist. In case of confirmed hormonal deficiency, an adult or pediatric endocrinologist is involved in the examination.
When making a diagnosis, Addison’s disease, familial isolated glucocorticoid deficiency (FIGD), adrenal hypoplasia are excluded. The pathology of lacrimation in Allgrove’s disease must be differentiated from Sjogren’s syndrome. The combination of the pathognomonic triad with neurological disorders requires differential diagnosis with polyneuropathies, adrenoleukodystrophy, congenital pathologies of the brain and spinal cord.
As with other genetic syndromes, the etiotropic treatment scheme for the disease has not yet been developed. Hormone replacement therapy with glucocorticoids comes to the fore. Lifelong intake of hormones stabilizes the patient’s well-being and prevents the development of an addisonic crisis. With a combined deficiency of mineral and glucocorticoids, treatment is carried out with combined drugs. For the correction of alacrimia, drops of “artificial tear” are prescribed.
The possibilities of drug treatment of neurological symptoms are limited by neuroprotectors, vitamins, antioxidants and metabolic therapy. In practical pediatrics, a significant role is played by the rehabilitation of patients with the involvement of a speech therapist, a child psychologist, a correctional teacher. Given the mild degree of intellectual disabilities, with appropriate treatment, socialization and professional realization of patients is possible.
The correction of esophageal pathology requires the help of surgeons. Endoscopic balloon esophagodilation is recognized as a gentle method of treatment, which improves the patency of food into the stomach, but has an unstable effect. The “gold standard” for achalasia is considered to be the Geller esophagocardiomyotomy, which shows good long-term results without relapses.
Prognosis and prevention
The disease is characterized by slow progression, therefore, with timely diagnosis and correction of adrenal insufficiency, the condition of patients remains stable. The long-term prognosis depends on the severity of neurological disorders, the presence of mental retardation. Prevention of the disease involves medical and genetic counseling for couples who have a high risk of having a child with Allgrove syndrome.