Introduction to rare skeletal disorders

Skeletal disorders are classified as inherited disorders with significant skeletal involvement resulting in abnormal bone length, density or shape. Most of them are rare—which is defined in Europe as less than 1 in 2000 people being affected—and some are extremely rare affecting only a tiny number of patients worldwide [1,2,3]. The current nosology and classification of skeletal disorders comprises more than 450 different skeletal diseases which are grouped in 42 different groups based on their clinical, radiological and/or genetic phenotypes [2].

The clinical phenotype in skeletal disorders is highly variable regarding severity, final body height and extraskeletal involvement. Severity in skeletal disorders ranges from perinatal lethality to very mild phenotypes such as premature degenerative joint disease or isolated mild short stature. Remarkable disproportionate short stature is a common feature in several skeletal disorders, but also normal stature and even tall stature is noted in some skeletal disorders [2, 4]. Extraskeletal involvement can be the clue to establish an accurate diagnosis [3, 4], such as cardiac defects (ciliopathies), cleft palate (type II collagenopathies; congenital glycosylation disorders with skeletal involvement), immunodeficiency and hematological abnormalities (cartilage hair hypoplasia; cell cycle defects, Fanconi anemia syndromes, Shwachman–Diamond syndrome), or severe myopia (type II collagenopathies) Table 1.

Table 1 Skeletal disorders: clinical and imaging workup and diagnostic clues
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In addition to clinical heterogeneity, the molecular spectrum of skeletal disorders is very broad. The more than 430 skeletal disorder causing genes are functionally diverse, affecting critical steps in bone and cartilage development as well as extraskeletal functions such as regulating metabolic pathways, cell division, gene transcription, or intracellular trafficking. The detailed function of several skeletal- disorder-causing genes has not been elucidated yet [2]. Within one and the same gene, different pathogenic variants can cause different skeletal disorder phenotypes: variants in the COL2A1 gene cause more than ten different type II collagenopathy phenotypes, ranging in severity from severe perinatal lethality to isolated premature arthrosis in adults [5]. On the other hand, one skeletal disorder phenotype can be caused by pathogenic variants in several different genes: ciliopathies with major skeletal involvement are clinically characterized by a narrow thoracic cage, short and horizontally layered ribs, shortened tubular bones and by a characteristic radiological patterning on skeletal radiographs of the pelvis (Fig. 1) and can be caused by pathogenic variants in more than 20 different genes [6, 7]. In addition, a large number of rare genetic syndromes present with prenatal or postnatal onset of short stature but without significant skeletal involvement [8], which adds complexity to the diagnostic approach in skeletal disorders.

Fig. 1
figure 1

Establishment of diagnosis in rare skeletal disorders using the three pillar approach. a Clinical, imaging and genetic testing is followed by clinical correlation to establish a diagnosis. The main goal is to establish a diagnosis based on correlation of all three pillars. Tissue banking, at least banking of fibroblasts, is strongly recommended in all critically ill patients and is suggested in patients with negative or inconclusive genetic testing or potential novel diseases to facilitate functional confirmation. b Examples for clinical, imaging and genetic pattern recognition in well-known skeletal disorders

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For all these reasons making an accurate diagnosis in skeletal disorders can be challenging. However, for clinical care of patients with skeletal disorders, it is crucial to establish a rapid and precise diagnosis to offer a disease-specific multidisciplinary therapeutic approach [2, 4, 9].

Here we describe the postnatal approach to diagnosis and management of patients and families with rare skeletal disorders by the multidisciplinary team of the Health Care Provider 1 (HCP1) at the Vienna Bone and Growth Center.

Combined clinical, radiological and genetic diagnostic approach

The diagnosis of skeletal disorders is usually based on a three pillar system including clinical, imaging and genetic analyses [2,3,4, 10,11,12]. The main goal of the diagnostic approach is to establish a clinical, imaging and genetic confirmed diagnosis of the skeletal disorder, to offer disease-specific patient management as well as disease-specific medical and genetic counseling to patients and families (Fig. 1a).

We established a systematic approach for the postnatal diagnostic workup of skeletal disorders, which is outlined in Fig. 1a and 2. It requires a detailed patient history, careful clinical examination of the patient and their family, as well as a complete skeletal radiographic evaluation (Table 1) to determine the clinical and radiographic pattern in skeletal disorders (Fig. 1b). Familiarity with skeletal disorders and other rare pediatric diseases as well as good pattern recognition skills are mandatory for establishing an accurate clinical and radiological diagnosis.

Fig. 2
figure 2

Postnatal diagnostic flow chart for skeletal disorders. Need for special disease management and monitoring for treatable complications should be evaluated at every patient contact and should not be postponed until the result of genetic testing is available. Need for urgent testing: critically ill patients, if results of genetic testing will influence the therapeutic management, pregnancy in patients or in a potential carrier. Trio genetic testing is preferred whenever possible to increase the chance of finding a definitive diagnosis and better interpretation of results. Targeted testing may be efficient when the clinical and radiological patterns indicate a very specific diagnosis and causative genes are not too large (e.g., achondroplasia), when a familial disease-causing variant is known, or when certain variants are more common in a population. CES clinical exome sequencing, CMA chromosomal microarray analysis, PID pre-implantation diagnostic, PND prenatal diagnostic, RNA ribonucleic acid, WES whole exome sequencing, WGS whole genome sequencing

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Genetic testing is the third diagnostic pillar in the diagnostic approach of skeletal disorders. Novel genetic techniques, such as massively parallel sequencing technologies, have revolutionized diagnostics in skeletal disorders and have had a huge impact on counseling of patients and families as well as on therapeutic decision making [2, 9]. Thus, being familiar with these novel genetic techniques is important for state-of-the-art patient care and should be available at highly specialized centers [9].

Massively parallel sequencing technologies allow extremely fast sequencing of the whole exome (whole exome sequencing, WES) or of targeted parts of the exome (clinical exome sequencing CES; panel analysis PA) in a single assay in the patient (mono-investigation) or in the patients and their parents (trio-investigation). Thereby detection of disease-causing variants—including single nucleotide variants (SNVs), small insertion or deletion (Indel), and copy number variants (CNVs)—is fast and highly cost-effective [13]. In addition, chromosomal microarray (CMA) is applied to exclude unbalanced chromosomal aberrations. In the near future, novel techniques, such as whole genome sequencing (WGS), will presumable replace CMA, CES, PA and WES due to diagnostic superiority [2, 14].

In recent years, these novel genetic techniques have become the first-tier diagnostics for rare monogenetic phenotypes and therefore have replaced a detailed clinical investigation and more invasive diagnostic procedures in many medical disciplines [14]. In contrast interpretation of genetic data in skeletal disorders often requires detailed clinical and radiological phenotyping, implying a combined clinical, radiological and genetic workup as the best first-tier diagnostic approach in skeletal disorders [2, 12]. Even in skeletal disorders which can be diagnosed based only on clinical or radiological patterning, genetic confirmation is recommended, as identification of the disease-causing variant is mandatory for therapeutic decisions (e.g., osteogenesis imperfecta) and molecular prenatal and preimplantation diagnostics (PND, PID) (e.g., Schneckenbecken dysplasia or ciliopathies) [9].

The key step within the diagnostic approach to skeletal disorders is the clinical correlation of clinical, imaging and genetic data to define a final diagnosis. Within the working group for rare skeletal disorders and unknown syndromes at the Vienna Bone and Growth Center, this is established in close collaboration of a highly specialized pediatrician and a human geneticist (Fig. 2). Sometimes rare and extremely rare skeletal disorders require consultation with an international expert panel to establish an accurate diagnosis (Fig. 2 and 3).

Fig. 3
figure 3

Postnatal multidisciplinary management for skeletal disorders. a Management of rare skeletal disorders at the HCP1 Vienna Bone and Growth Center. Patient support groups and social media are an additional important source for many patients and their families. b Skeletal disorders affect skeletal and variable extraskeletal systems. Optimal management requires a disease-specific multidisciplinary team approach. HCP health care provider

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Multidisciplinary management approach

It is strongly recommended that patients with rare skeletal disorders should be managed in highly specialized centers, such as the European Reference Network on rare bone diseases [15]. This should improve access to high-quality healthcare for patients and their families and should facilitate the generation of reliable data on rare skeletal disorders in order to improve further treatment strategies [9, 15]. In recent years, specific treatments have been developed for a small number of skeletal disorders [9, 16], but for the majority of skeletal disorders current treatment options consists of symptomatic approaches and in monitoring for treatable complications [2, 9].

Skeletal disorders are associated with a highly variable range of clinical and nonclinical challenges for patients, families and health care providers and therefore need a multidisciplinary management approach [2, 9, 17]. The multidisciplinary management approach for skeletal disorders and their families at the HCP1 Vienna Bone and Growth Center is outlined in Fig. 3. Additional care by a multidisciplinary team close to the patient’s home (local health care provider) is desirable, especially if the patient lives far away from the Vienna Bone and Growth Center. Multidisciplinary management of rare skeletal disorders requires coordination of diagnostic and therapeutic issues for each patient. For coordination issues one specialized pediatrician from the HCP1 Vienna Bone and Growth Center, who is experienced in managing this disorder, is defined as the primary case coordinator for each patient (medical case manager). This case manager is responsible for providing advice regarding local health care providers for local disease-specific management, to coordinate patients’ diagnostic and therapeutic approaches within the Vienna Bone and Growth Center, to perform database searches, and—if necessary—to communicate with expert panels and research groups (Fig. 3a). The multidisciplinary team for skeletal disorders at the Vienna Bone and Growth Center includes all disciplines needed for patient care. Besides access to all medical subdisciplines, to several diagnostic techniques and to specialized therapies (e.g., physio-occupational and speech therapy, and nutrition and dietary treatment to prevent obesity), it is important to offer social work, genetic counseling, psychological advice and crisis intervention to patients and families (Fig. 3b).

Furthermore, it is important to remember that suffering from a rare disorder often starts with a diagnostic odyssey, followed by persistent and significant burden to patients and their families [17]. A multidisciplinary management approach in highly specialized centers should be directed by high-quality healthcare as well as by awareness that patients and their families need constant multidisciplinary support to cope with medical, psychological, social, financial and further burdens of rare diseases.

Conclusion

Skeletal disorders comprise a very heterogeneous group of rare and extremely rare genetic disorders with major skeletal involvement. Standardized diagnostic and management approaches in highly specialized centers are recommended for optimal patient care.