Clinical and radiographic characteristics of pycnodysostosis: A systematic review

Pycnodysostosis (PYCD), also known as Toulouse-Lautrec syndrome, was first reported as a distinct condition by Maroteaux and Lamy in 1965. This rare autosomal recessive disorder is characterized by osteosclerotic dysplasia of the skeleton. PYCD arises from the mutation of the gene that encodes the enzyme cathepsin K, which is located on chromosome 1q21. This leads to a reduction in the enzyme’s activity.1, 2 As a consequence of this enzymatic deficiency, individuals with PYCD have bones that are abnormally dense and brittle due to impaired bone remodeling processes.3

Parental consanguinity is found in approximately 30% of patients diagnosed with PYCD, which has an estimated incidence of 1.7 cases per 1 million births. While it is typically identified at an early age, diagnosis can sometimes be delayed. In those cases, the condition may be detected based on a propensity for bone fractures and infections, which are consequences of increased bone density and compromised bone vascularization.3, 4

Common clinical features of PYCD include short stature, prominent nose, acroosteolysis of the distal phalanges, bluish sclera, and hypoplasia of the midface. Additionally, reports frequently indicate craniofacial radiographic findings, such as delayed cranial suture closure, open fontanelles, lack of pneumatization in facial sinuses, and the presence of frontal and parietal bosses.4, 5 Moreover, due to impaired bone remodeling, patients with PYCD face an elevated risk of pathological fracture during dental procedures. This can lead to osteomyelitis, considered the most serious oral complication associated with this syndrome.4, 5, 6 Several oral characteristics are also important to note in the diagnosis and management of PYCD, including maxillary atresia, obtuse mandibular angle, enamel hypoplasia, hypercementosis, malocclusion, delayed eruption, anodontia, narrow and grooved palate, and ectopic teeth.5

Although the understanding of PYCD and genetic testing for this condition have advanced considerably, diagnosis is still based primarily on clinical and radiographic characteristics.7 Consequently, this systematic review was conducted to evaluate and discuss the predominant clinical and radiographic craniofacial and oral features of PYCD. This approach was designed to elucidate the patient profile associated with PYCD and facilitate early diagnosis.

The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/prospero/), under the protocol number CRD42023398001. This paper was composed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.8

The search terms were developed using the PICO methodology (representing the participants, intervention, control intervention, and outcome measures), which guided the formulation of the following research question: “What are the most common clinical and radiographic craniofacial and oral alterations in patients diagnosed with PYCD?”

An electronic literature search, without time or language restrictions, was performed from February to March 2023 across the following databases: PubMed/Medline, Web of Science, Science Direct, Scopus, Embase, and the Cochrane Collaboration Library. Additionally, OpenGrey and Google Scholar were utilized to explore the gray literature. Manual searches were also performed by cross-referencing the bibliographies of the identified articles. The search strategy employed a combination of the following keywords: pycnodysostosis OR pyknodysostosis OR Toulouse-Lautrec syndrome.

Craniofacial alterations are frequently observed in individuals with PYCD, an autosomal recessive syndrome. This condition involves the mutation of the gene that codes for cathepsin K, leading to an imbalance in the bone remodeling process.2, 72 According to the present findings, PYCD is relatively prevalent in Asia, with the highest rates observed in India, Egypt, and Brazil. These findings align with those reported by Moreira Júnior et al.5

Previous research has underscored the high rate of consanguinity among the parents of individuals diagnosed with PYCD, consistent with the autosomal recessive inheritance pattern of the disease.4, 13, 37, 49, 72, 87

According to Sayed Amr et al.,13 patients with PYCD typically seek medical attention for concerns such as short stature or unusual bone fractures. In this review, short stature was frequently observed as a clinical feature in the analyzed reports, occurring in 86.1% of cases. Additionally, brachydactyly was present in 66.0% of cases, and acroosteolysis was noted in 58.1%. While previous studies10, 13, 17, 31, 50 have identified sleep apnea among characteristics of PYCD, it was not commonly observed in this systematic review, appearing in only 13.5% of the reported cases.

The diagnosis of PYCD primarily relies on clinical and radiographic features, as genetic testing is inaccessible through many health services.4, 7 The present systematic review enabled the identification of common craniofacial clinical manifestations in patients with PYCD, including midfacial hypoplasia, blue sclera, exophthalmos, and prominent nose. These distinguishing features are crucial for diagnosing the condition, particularly because clinical diagnosis is essential when complex, specific, and expensive genetic tests are not available to patients with limited financial resources.

According to Schmidt et al.,72 plain radiographs - including those of the skull, hips, femurs, hands, and feet - interpreted by an experienced radiologist are frequently adequate to suggest a diagnosis of PYCD, even in the absence of clinical symptoms.

Therefore, it is important to highlight that the findings of the present systematic review identified the primary craniofacial imaging features of PYCD. These features include delayed cranial suture closure, open fontanelles, cranial bosses, and high bone density. While delayed suture closure is a prominent feature of PYCD, craniosynostosis has also been documented as a characteristic of the condition in prior research.4, 13, 19, 59, 64 Nonetheless, craniosynostosis was observed infrequently in the studies covered by this systematic review, occurring in only 13.4% of cases.

Obtuse mandibular angle, a key diagnostic feature that distinguishes PYCD from cleidocranial dysplasia, was observed in 84.3% of the present sample. This observation supports the findings of Sayed Amr et al.,13 Doherty et al.,7 Markova et al.,49 Sait et al.,4 and Verma and Singh.87

Few studies have been published that describe the oral clinical and radiographic changes associated with PYCD.5, 13, 57, 59 In this systematic review, the most frequently observed oral abnormalities were micrognathia (found in 62.6% of cases), malocclusion (59.2%), and dental crowding (54.2%).

Previous research5, 13, 59 has indicated that patients with PYCD can exhibit multiple dental anomalies, including enamel hypoplasia, obliterated pulp chambers, delayed eruption, tooth agenesis, hypercementosis, and ectopic teeth. In the present review, tooth agenesis was the most frequently observed anomaly, present in 15.6% of the 179 cases evaluated. Notably, most articles assessed in this review did not provide information on clinical and dental examinations of patients, which may have resulted in underreporting of these anomalies.

Patients diagnosed with PYCD experience an impaired capacity to effectively remodel bone, leading to a generalized increase in bone density and sclerosis. This condition increases their susceptibility to bone fractures; however, these fractures tend to occur in the long bones.4 In the present systematic review, only 7 of the 179 patients exhibited fractures of the craniofacial bones.

Among the oral manifestations noted in patients with PYCD, osteomyelitis is the most serious. In the gnathic bones, local factors associated with the development of osteomyelitis include continuous trauma, alveolar surgical intervention, and infection.5, 6 Severity aside, the present systematic review revealed a relatively low frequency of osteomyelitis in the maxillary bones, affecting 7.3% of the examined cases.

According to a systematic review carried out by França et al.,6 tooth extraction was identified as the primary risk factor associated with the development of osteomyelitis in patients with PYCD. This was followed by a history of mandibular fracture and the presence of infections, including caries and periodontal disease. In terms of anatomical location, the mandible was the most frequently impacted bone. The most common symptoms observed were edema, pain, purulent discharge, fistula formation, and trismus. Treatment for osteomyelitis can vary from conservative methods, such as antibiotic therapy and curettage, to more aggressive strategies, including tooth extraction and surgical resection.

The current approach to managing PYCD is multidisciplinary and focuses primarily on managing symptoms, with an emphasis on fracture prevention. To prevent osteomyelitis, clinicians should convey the importance of daily oral hygiene, while providing antibiotic prophylaxis in cases of tooth extraction.16 Dental professionals should be aware of the primary characteristics of PYCD, as this knowledge is key to early diagnosis of the syndrome. Early detection enables more effective management and helps prevent subsequent complications, improving patient quality of life.

The heterogeneity of the studies included in this systematic review precluded the use of meta-analysis for statistical evaluation of the data gathered. Nevertheless, despite this limitation, the study provides a comprehensive examination of the clinical and imaging features of PYCD, establishing the principal characteristics for its early diagnosis.

The findings of this systematic review confirm that PYCD is a rare condition that predominantly affects children of consanguineous parents. Female patients were slightly more common than male patients, and the mean age fell within the second decade of life. PYCD is characterized by short stature, acroosteolysis, brachydactyly, prominent nose, exophthalmos, and hypoplasia of the middle third of the face. Notable oral and craniofacial abnormalities include an obtuse mandibular angle, frontal bosses, open fontanelles and cranial sutures, and increased bone density in the craniofacial region. Patients may also exhibit micrognathia, malocclusion, dental crowding, and a narrow, grooved palate.