Introduction
Toulouse-Lautrec syndrome, also known as Pycnodysostosis, having first been described by Maroteaux and Lamy in 1962, is a rare disorder where the bones do not grow normally, and are unusually thick; but are also weak and prone to fractures. It was named after a famous painter who too was afflicted by this disorder, Henry de Toulouse-Lautrec. It was not until 1996 that the gene responsible for Pycnodysostosis was discovered, leading not only to an accurate diagnosis, but also to the carrier testing as well as to the better understanding of this disease. This syndrome consistently causes short stature, where people who suffer from this disease are short; the height of an adult male with Pycnodysostosis is relatively lesser than 150 cm, with adult females who have the syndrome being even shorter. This syndrome is said to occur with equal frequency in men and women. Two copies of the defective gene are required to cause symptoms. Deficiency of cathepsin K, which primarily, is an enzyme that cleaves protein, and which occasions a mutation in the gene that codes the enzyme, is known to cause the syndrome. This enzyme is critical for the formation of healthy bone cells known as osteoclasts, which are responsible for resorption into the bone and help in building new bones. Notably, Pycnodysostosis disrupts the normal functioning of osteoclasts in most of the afflicted patients, owing to the lack of cathepsin K. Usually, this leads to the inadequate resorption of organic matrix, a component of the bone (Alves, Cantin, & Cantin 2014). Pycnodysostosis can be categorized in the large group of genetic diseases which are uncommon, but are collectively significant because of their huge impact on the affected individuals. There is no given treatment provided for this disorder; the treatment is only supportive and as such, it is important to take care of those affected, as this prevents and as well, minimizes tendencies for fractures to occur since this, primarily, is the most expressed of all the threats that are faced by those affected by Pycnodysostosis. This disorder is not a life threatening condition, although its severity regarding height, frequency of fractures or other additional abnormalities may cause significant suffering to the patient.
Once a proper diagnosis of the syndrome is made, the patients can live a normal life expectancy. Often, the condition is diagnosed in childhood. However, the syndrome may at times not be detected until adulthood, which is usually after a series of examinations or constant fracturing of the bones. Basically, diagnosis is clinical and includes the performance of confirmatory radiographic examination of the skeleton and skull of the affected individuals, and in their entirety; there are different diagnoses taken which include cleidocranial dysplasia, osteopetrosis, and idiopathic acro-osteolysis (Bor, Rubin, & Rozen 2011). This is because it is possible to confuse Pycnodysostosis with other diseases as they present similar signs; it is therefore important to make a differential diagnosis in order to give the best treatment for each patient. In osteopetrosis, the bone marrow is sometimes absent which is a leading cause for hematopoietic alteration appearance. Also, it shows signs of cranial nerve compression like deafness and facial paralysis. In idiopathic acro-osteolysis, patients are characteristically typified by an upturned nose and also, by hypotelorism. Also, the angle of the mandible is acute with the absence of increased bone density. Finally, cleidocranial dysplasia displays alterations of the skeletal bone membranes, even though bone density, more often than not, remains unincreased (Rajan, Singh, Joshi, & Bhave 2015). The disease has been described all over the world which is said to affect all races regardless of gender or age.
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The disease is mainly caused by the lack of cathepsin K. Cathepsin K degrades collagen and other bone proteins. The protein encoded in this gene is a lysosomal cysteine protease, which is involved in bone remodeling and resorption. For patients with this disease, nonsense, missense and stop codon mutations in the gene encoding cathepsin K are present (Bor, Rubin, & Rozen 2011). With respect to bone mineral degradation, osteoclasts are not functional to those patients with Pycnodysostosis, owing to mutations in the cathepsin K gene. Therefore, any hope for the development of future therapies with respect to this syndrome is heavily reliant on understanding the regulation and role of cathepsin K. Furthermore, the cathepsin inhibitors will be utilized in pathological processes that will enhance activation and bone resorption. In the light of research and innovation, several cathepsin K inhibitors have been developed and evaluated in clinical studies. However, the development of some inhibitors has been terminated due to severe side effects of these inhibitors on the patients despite their effectiveness in reducing bone resorption markers (Voisin, Bianchi, Balon-Perin, & Glineur 2009). It is clear that more studies are required to understand better the mechanism of the observed side effects so as to come up with better inhibitors which have higher efficiency and are selective to ensure that as they inhibit the collagen matrix, they do not affect the other activities of another protease. Cathepsin K plays a significant role in the immune system which could serve as the solution to the patients of Pycnodysostosis.
Signs and Symptoms
Pycnodysostosis is a recessive disorder; this implies that an infant must inherit two mutant copies of the gene, one from each parent so as to suffer from the disease. For instance, Toulouse-Lautrec, who the syndrome is named after was born to parents who were first cousins. It causes the bones to be abnormally dense, unusually short and delays the normal closure of the connections of the skull bones in infancy. This causes the soft spot on top of the head to remain open; moreover, the people with this syndrome have their jaw and collar bone prone to fractures. Other abnormalities include the skin, nails, collar bones and teeth; it can also cause slow deterioration of the distal phalanges (Ortegosa, Bertola, Aguena, Passos-Bueno, Kim, & de 2014). In addition to irregular nails, the disorder is also associated with anemia. The syndrome is also characterized by underdeveloped facial bones and a tendency to suffer from dental cavity.
Early and delayed radio-clinical manifestations of Pycnodysostosis is of the essence since the syndrome resembles cleidocranial dysostosis and osteopetrosis. The features which differentiate it are short stature, generalized diffuse osteosclerosis, and sclerosis of the terminal phalanges and history of multiple fractures of long bones. Other features include wrinkled skin, history of repeated chest infections, sleep apnea, hypoplastic midface and beaked nose. Also, there are other dental abnormalities such as decayed, poorly located, or abnormally shaped teeth, and delayed tooth eruption, which are observed in the patients affected by this disease (Alves, Cantin, & Cantin 2014). Radiographic examination of patients with this syndrome shows an increased density of bones of the entire skeleton, delayed closure of cranial sutures with dental irregularities present in the skull films.
Treatment
Although there is no specific treatment of Pycnodysostosis, Precautions like taking great care when handling a child affected by the disease, exercises, and activities which are light and do not require too much impact should be observed. In addition, dental hygiene and regular dental visits play a significant role in the lives of people with this syndrome, as this helps in the management of any associate dental anomalies. Tooth extraction demands special care due to fracturing risks, especially in the mandible because of the weak bones; bone healing is, however, normal despite the high frequency of fracturing. For children affected by Pycnodysostosis, they should receive special care, particularly preventive treatment because of possible alteration and for follow-up of the craniofacial development. The prognosis pycnodysostosis is good with no systemic alterations noted and depends on the features of the individual. The treatments may include therapy to enhance height, routine dental care, orthopedic observations, medical care for bone fractures, avoidance of high impact activities, consideration of surgeries and breathing assistance (Bor, Rubin, & Rozen 2011). Moreover, for a person to be affected with this disorder, the individual must receive mutated genes from both parents; each parent should provide a mutated gene. A person with one mutated copy is referred to as a carrier and does not have the features of this condition.
Conclusion
The existence of genetic diseases in the population usually indicates the duration of existence of the mutated genes in humanity. The scarcity of Pycnodysostosis may be as a result of a more recent mutation as ancient mutations spread widely through the population migrations. Patients with Pycnodysostosis should be carefully examined through the radiographic and clinical features to ensure proper diagnosis. Under-diagnosis of this condition is a major issue; more research is required to understand the syndrome better. Active examination of hearing capabilities and eye test to people affected by Pycnodysostosis should be carried out to determine the impact of this syndrome as some patients have shown hearing loss and poor eyesight. Special emphasis should be accorded to maintain good oral hygiene with frequent dental visits. Although biochemical and genetic knowledge in the field of Pycnodysostosis is improving, the clinical and radiological features are still the basis of diagnosis for this disease. It is crucial for the early detection of this disease to plan for the treatment soon enough and more suitably to provide a better quality life to the patients. Specific treatment for this disease should be established early to help improve the quality of life of the patients and prevent more complications since we are in the era of advanced molecular research. Patients affected by this disease should always be informed about the possible risks and complications before undergoing surgical procedures.
References
Alves, N., Cantin, M., & Cantin, M. (March 30, 2014). Clinical and radiographic maxillofacial features of pycnodysostosis. International Journal of Clinical and Experimental Medicine, 7, 3, 492-496.
Bor, N., Rubin, G., & Rozen, N. (January 01, 2011). Fracture management in pycnodysostosis: 27 years of follow-up. Journal of Pediatric Orthopedics. Part B, 20, 2, 97-101.
Ortegosa, M. V., Bertola, D. R., Aguena, M., Passos-Bueno, M. R., Kim, C. A., & de, F. M. E. (January 01, 2014). Challenges in the orthodontic treatment of a patient with pycnodysostosis. The Cleft Palate-Craniofacial Journal: Official Publication of the American Cleft Palate-Craniofacial Association, 51, 6, 735-9.
Rajan, A. R., Singh, V., Joshi, C. S., & Bhave, A. A. (October 01, 2015). Pycnodysostosis: A rare cause of short stature. Medical Journal Armed Forces India, 71, 4, 393-395.
Voisin, C., Bianchi, F., Balon-Perin, A., & Glineur, R. (May 01, 2009). Pycnodysostosis: a case report, a brief review of the literature and our treatment strategy. International Journal of Oral and Maxillofacial Surgery, 38, 5, 495.
