Pachydermoperiostosis is a genetically heterogeneous disease that manifests itself as a complex lesion of the skin, joints, bones and a number of internal organs. Symptoms of this condition are hyperplasia of all layers of the skin, hyperhidrosis, disorders of the cardiovascular system, deformation of the distal phalanges of the fingers like “drumsticks”. Diagnosis of pachydermoperiostosis is carried out on the basis of patient examination data, X-ray and biochemical studies, study of hereditary history and molecular genetic analysis. There is no specific treatment for the disease, but symptomatic measures can restrain its development for a long time.
Pachydermoperiostosis (primary hypertrophic osteoarthropathy) is a hereditary disease with a different (according to recent discoveries in the field of genetics) inheritance mechanism, affecting the skin, musculoskeletal system and cardiovascular system. According to some sources, this condition was first described in 1868 by G. Friedreich, but its full-fledged study and definition as a separate nosological unit was carried out by A. Touren only in 1935. The main reason for such a long inability to determine pachydermoperiostosis as an independent disease was that many of its manifestations are similar to secondary (symptomatic) disorders caused by lung and heart damage or oncological processes. This pathology affects men much more often (the sexual distribution of patients is 8:1) and at the same time, it is generally harder for them than for women. The occurrence of pachydermoperiostosis is currently not precisely determined – the main obstacles to this are frequent erroneous diagnosis with symptomatic forms and the presence of erased variants of the disease observed in heterozygotes.
Causes and classification
The study of the etiology and pathogenesis of pachydermoperiostosis lasted a very long time, only in 2008 it was possible to identify the first gene responsible for the development of this disease. It is HPGD, located on the 4th chromosome and encoding the enzyme NAD+-dependent 15-hydroxy-prostaglandin dehydrogenase. The function of this protein is the dehydration of prostaglandin E, the process is considered an important link in the metabolism and utilization of this biologically active substance. As a result of HPGD mutation, this process is disrupted, the concentration of prostaglandin increases, which is the cause of the development of pachydermoperiostosis. Currently, there is a discussion among geneticists about the mechanism of inheritance of mutations of this gene – most tend to believe that it is autosomal recessive. But the presence of erased symptoms of pachydermoperiostosis in heterozygotes for the defective HPGD gene gives grounds for some specialists to claim autosomal dominant inheritance with incomplete penetrance. A variant of this pathology caused by HPGD mutation was called primary hypertrophic osteoarthropathy type 1.
Another form of pachydermoperiostosis was discovered shortly after the identification of the HPGD gene – it turned out that some patients with proven familial pathology do not have such genetic defects. As a result, primary hypertrophic osteoarthropathy of the 2nd type was revealed, due to a mutation of the SLCO2A1 gene localized on the 3rd chromosome. The expression product of this gene is a transmembrane protein that facilitates the transport of prostaglandin molecules through biological membranes. A violation of the structure of this protein caused by genetic defects leads to a deterioration in the transport of prostaglandins and their accumulation in the bloodstream, which, as in the previous case, is the cause of pachydermoperiostosis. Forms of this disease caused by mutation of the SLCO2A1 gene are inherited by an autosomal recessive mechanism.
Currently, there is also a poorly studied autosomal dominant variety of pachydermoperiostosis. It is the most rare, and its etiology is still unclear – according to some data, it may be both variants of HPGD mutation and damage to other, as yet unidentified genes. Clinical studies of such patients (in particular, the determination of prostaglandin E levels) indicate that the pathogenesis of this form of pachydermoperiostosis differs little from other types of the disease, but has a pronounced autosomal dominant nature of inheritance.
Pachydermoperiostosis is characterized by a rather diverse clinical picture, especially with regard to the first symptoms of the disease. In most cases, manifestations of pathology can be detected already in the first few years of a child’s life, but they become most pronounced by adolescence. Cases of the development of symptoms of pachydermoperiostosis in adults who were previously phenotypically healthy have been described. In the case of an early onset of the disease, one of the first manifestations will be a violation and delay in the overgrowth of the fontanelles on the skull, in the future dermatological symptoms will join. These include an increase in the thickness of the skin on the face, head, hands and feet, the development of their folding, sometimes in combination with hyperkeratosis. Eyelids suffer quite strongly with pachydermoperiostosis – there is a thickening of the cartilaginous base and skin, conjunctival dystrophy, the development of cysts from the tarsal glands. Pronounced palmar and foot hyperhidrosis is also characteristic.
Lesions of the musculoskeletal system in pachydermoperiostosis, in addition to a violation of the formation of the skull, are reduced to thickening of long tubular bones due to periostosis, arthralgias, sometimes contractures of the joints. A typical sign of the disease is the deformation of the distal phalanges of the fingers of the hand with the formation of “drumsticks” and nails in the form of “watch glasses”. In some cases, swelling in the knee and elbow joints may be registered. Of the general manifestations of pachydermoperiostosis, a depressed state, weakness, lag in physical development are noted – some of these symptoms may be due to a heart defect (open arterial duct), which is also characteristic of this disease. Sometimes patients may have mental disorders (depression, isolation, phobias), most often caused by aesthetic problems caused by this pathology – skin changes, hyperhidrosis and others.
To determine the presence of pachydermoperiostosis, data from the examination of the patient, the study of his hereditary anamnesis, X-ray and molecular genetic studies, biochemical blood analysis are used. During the examination, the dermatological manifestations of the disease primarily attract attention – hypertrophy of the skin on the head, face and limbs, increased greasiness and related disorders (acne, blackheads), hyperhidrosis. The deformation of the fingers in the form of “drumsticks” is determined, with the thinness of the patient, it is also possible to detect thickening of long tubular bones, especially in the area of metaphyses. Sometimes there is swelling and soreness of the joints, patients with pachydermoperiostosis complain of bone pain, fatigue, bruising. Histological examination of the skin reveals a sharp thickening of all its layers, an increase in the number of collagen fibers, the size of sebaceous and sweat glands.
X-ray examinations may indicate non-infection of the cranial fontanelles (in young children) and thickening of the bones due to periostosis. The surface of the bones is rarely smooth, more often fringed or needle-like. In adults, changes and defects in the bones of the skull with pachydermoperiostosis, as a rule, are not determined. General and biochemical blood tests for this disease also do not detect any pathological changes, but a specialized study reveals an extremely high level of prostaglandin E. Molecular genetic diagnosis of pachydermoperiostosis is performed by automatic sequencing of HPGD or SLCO2A1 gene sequences in order to detect mutations, prenatal determination is possible. An examination of the heart (for example, an echocardiogram) can confirm the presence of such a defect as an open Botall duct. Differential diagnosis should be made with secondary forms of this condition, therefore, all patients must undergo a lung examination – especially for a malignant tumor.
There is no specific treatment for pachydermoperiostosis, symptomatic therapy is used, sometimes corrective measures are taken. To reduce the severity of symptoms, corticosteroids are prescribed (both systemically and topically, in the form of ointments or medicinal electrophoresis), drugs that improve tissue trophism. To reduce joint pain and improve the general condition of patients with pachydermoperiostosis, nonsteroidal anti–inflammatory drugs are used – diclofenac sodium, ibuprofen, indomethacin. They not only have an analgesic effect, but also inhibit the formation of prostaglandins by blocking the enzyme cyclooxygenase. To reduce the severity of hyperhidrosis, local antiperspirants and techniques such as botulinum therapy are used.
In some cases, surgical interventions are resorted to to eliminate the manifestations of pachydermoperiostosis. First of all, this applies to the correction of heart defects – for this, an operation is performed to close the arterial duct. Plastic surgery techniques can also be used to eliminate pronounced aesthetic deficiencies caused by dermatological manifestations of the disease. Surgical orthopedics is used in the case of joint contractures and other pronounced disorders of the musculoskeletal system resulting from pachydermoperiostosis.
Prognosis and prevention
In most cases, the prognosis of pachydermoperiostosis is unfavorable – there is no specific treatment for this disease, and its manifestations tend to progress. The defeat of the musculoskeletal system can lead to disability of patients, skin disorders are often complicated by secondary bacterial infection, undetected heart defects sometimes cause death. Nevertheless, adequate symptomatic therapy of pachydermoperiostosis can significantly weaken the manifestations of pathology and maintain the patient’s working capacity until old age. It is important to pay attention to the psychological state of patients, since often such a disease becomes the cause of pronounced mental problems and disorders. Prevention of pachydermoperiostosis is possible only within the framework of medical and genetic counseling before conception of a child and prenatal genetic diagnosis.