Hermansky-Pudlak syndrome is a hereditary disease caused by point mutations of the HPS1, HPS4, AP3B1 genes, etc. Pathology is characterized by congenital cellular immunodeficiency, disorders of platelet aggregation, depigmentation. Also, those suffering from Germansky-Pudlak syndrome have recurrent infections, pulmonary fibrosis, granulomatous colitis. Diagnosis of the disease involves immunological and genetic tests, ophthalmological examination, various methods of instrumental visualization. Symptomatic treatment: antibacterial, antifibrotic, immunocorrective therapy
General information
The disease in two unrelated patients was first described in 1959 in the works of Czech therapists F. Germanski and P. Pudlak, after whom it was named. Data on the prevalence of the disease are contradictory: the highest rate is observed in Puerto Rico (1:1800, taking into account the carrier in 5% of the population), and on average the syndrome occurs worldwide with a frequency of 1 case per 500 thousand people. Despite its rarity, pathology does not lose its relevance, it is actively studied by geneticists and molecular biologists.
Causes
The disease occurs with gene mutations, mainly appears sporadically in all ethnic groups, but cases of inheritance by autosomal recessive type have been described. Thanks to the development of modern genetics, scientists were able to identify 9 different molecular variants of the disease caused by mutations of specific genes. The most common are type 1 (HPS1), type 2 (AP3B1), type 4 (HPS4).
Pathogenesis
The most studied is the type 1 Hermansky-Pudlak syndrome associated with damage to the HPS1 gene. It encodes the formation of transmembrane protein, which is contained in intracellular organelles (lysosomes, melanosomes, dense platelet granules), contributes to their proper functioning. Since the gene defect disrupts the work of melanosomes, patients develop albinism, accompanied by decreased vision, photophobia, strabismus.
In Germansky-Pudlak disease, ceroid-lipofuscin complexes accumulate in immune cells of the phagocytic link, as a result of which their activity is disrupted. Histological examination in the parenchyma of internal organs and bone marrow determines a specific yellow granular substance. Hemorrhagic manifestations of the disease are associated with the pathology of the vital activity of megakaryocytes (platelet precursors).
Hermansky-Pudlak syndrome type 2 is characterized by a violation of the structure of the transmembrane protein adaptin beta-3A, which is ubiquitous in the body. It is necessary for the operation of a large subunit of the protein complex, delivering protein to lysosomes, melanosomes, dense granules. With a deficiency of this protein, platelet aggregation decreases, and immunodeficiency increases.
Symptoms
A typical sign of the disease is hemorrhagic diathesis caused by impaired platelet function. It is manifested by small spot hemorrhages on the skin and mucous membranes. In most cases, hemorrhagic syndrome is presented in a mild form, does not threaten the health of patients. With a more severe variant, spontaneous bleeding from the nose, gastrointestinal tract (vomiting with blood, melena), lungs (cough with an admixture of blood) opens. In women, uterine hemorrhages are possible.
The second pathognomonic sign of the Hermansky-Pudlak syndrome is oculocutaneous albinism. From birth, the child has excessively pale skin with a pinkish tinge due to translucent vessels. The eyes are a light blue shade, but under certain lighting they turn red. The hair on the head and on the body is white or pale yellow. Patients usually complain of decreased vision, strabismus, unpleasant sensations when staying in the bright sun.
In the 1st, 2nd, 4th and possibly 9th types of Germansky-Pudlak syndrome, primary cellular immunodeficiency is observed, caused by insufficiency of the phagocytic link of immunity. Patients are predisposed to frequent viral, bacterial and fungal infections, which often have a recurrent course, are resistant to standard etiopathogenetic treatment.
Complications
Given the severe deficiency of cellular immunity, the main problem for patients with Germansky-Pudlak syndrome is the generalization of infections. Most often, the process begins with prolonged pneumonia, which, with an unfavorable course, ends with sepsis, septic shock. In the absence of timely complex therapy, there is a high risk of death.
Due to the deposition of specific molecules in lysosomes, 68% of patients eventually develop symptoms of pulmonary fibrosis with respiratory insufficiency of the restrictive type, while 45% of patients show violations during chest radiography. With Hermansky-Pudlak syndrome, there is an increased risk of developing cardiomyopathy, chronic heart failure. In 15% of patients, the clinic of granulomatous colitis manifests itself.
Due to insufficient pigmentation, the skin of patients is extremely sensitive to ultraviolet light, even a short stay in the sun is fraught with extensive burns, photodermatitis. Due to the lack of a protective layer of melanocytes in the pigment epithelium of the retina, photophobia worries, sometimes turning into daytime blindness. Frequent bleeding can cause chronic iron deficiency anemia.
Diagnostics
The examination of the patient is carried out by a multidisciplinary team of specialists, which includes a dermatologist, hematologist, immunologist, geneticist. According to clinical manifestations, it is extremely difficult to establish a diagnosis, which is due to the rarity of the Hermansky-Pudlak syndrome, its similarity to Chediak-Higashi disease. The plan of diagnostic measures includes the following research methods:
- Ophthalmological examination. To clarify the presence and severity of eye damage, standard visometry, perimetry is prescribed. Ophthalmoscopy is also performed to study the condition of the fundus, examination with a slit lamp to detect lens lesions.
- Instrumental methods. Given the high frequency of respiratory infections and fibrosis, patients require radiography of the organs of the GC in 2 projections, CT of the lungs, spirography. To exclude organic causes of gastrointestinal bleeding, EFGDS, colonoscopy are used.
- Blood test. To clarify the nature of hemorrhagic phenomena, a standard hemogram, coagulogram is shown. To exclude tumor pathologies of the bone marrow, a biopsy can be used. To assess the nature of immunological disorders, an immunogram is made.
- Genetic testing. Since the genetic prerequisites of all types of Hermansky-Pudlak syndrome are precisely known, it is advisable to carry out genome sequencing to verify the diagnosis. As part of the medical and genetic consultation, the test is also recommended to the patient’s next of kin.
Treatment
Schemes of etiopathogenetic therapy of Germansky-Pudlak syndrome have not been proposed. The essence of medical care is to correct existing health disorders, prevent infectious and hemorrhagic complications. Accordingly, the following treatment options may be recommended for the clinical picture of the disease:
- Antibacterial therapy. Given the severity of the course of most infections, massive etiotropic therapy is prescribed at their first signs. As a rule, combinations of drugs and reserve antibiotics are used. For viral or mycotic infections, appropriate medications are used.
- Immunocorrection. To improve the immune status of patients, to prevent life-threatening generalized infections, colony-stimulating factors are introduced. Immunotherapy (T-cell therapy, hematopoietic stem cell transplantation) is considered a promising treatment option.
- Treatment of pulmonary fibrosis. Oxygen therapy has a high therapeutic potential, which reduces shortness of breath, increases the tolerance of physical exertion. From medications, glucocorticosteroids, antifibrotic drugs, bronchodilators are indicated.
- Protection of the organ of vision. To prevent the destructive effect of ultraviolet rays on the retina, patients need to wear glasses with high-quality light-protective glasses or special shaded contact lenses for life. In the presence of appropriate symptoms, correction of myopia, astigmatism is carried out.
Prognosis and prevention
Many patients, provided comprehensive and timely care, live to adulthood, but with severe immunodeficiency, mortality can occur even in infancy. The prognosis is determined by the genetic variant of the Hermansky-Pudlak syndrome, the degree of compliance with medical recommendations. Specific preventive measures have not been developed, family members of the patient need to consult a geneticist.