Skeletal and dental abnormalities in patients with sex chromosome aberrations: a systematic case-based review

INTRODUCTION

Most chromosome aberrations are associated with numerous abnormalities in somatic and mental development. Aneuploidy, defined as the occurrence of one or more extra or missing chromosomes in the typical diploid set, occurs in at least 5% of all pregnancies [1, 2]. Sex chromosome aneuploidies (SCAs) are the most common chromosomal anomalies, with a total frequency of 1 in 400 [3]. SCAs include conditions in which there is an abnormal number of sex chromosomes [4], such as Turner syndrome (45,X), Klinefelter syndrome (47,XXY), or Jacobs syndrome (47,XYY). These syndromes are a frequent cause of miscarriage in the first trimester of pregnancy.
Turner syndrome (TS) is a congenital genetic disease occurring in the female sex, with a prevalence of appro­ximately 1 in 2500 newborn girls [5]. The characteristic clinical picture is associated with quantitative and/or structural aberrations of the X chromosome. The features of TS were first described in 1938 by Henry H. Turner, an Oklahoma physician, who published a description of 7 women with short stature, sexual infantilism, congeni­tal webbed neck, cubitus valgus, and low hairline at the back of the neck [6]. However, earlier descriptions of this disease are known, e.g. by the Russian physician M.A. Shereshevky (1925) or the German paediatrician O. Ullrich (1930) [7, 8].
Another SCA, Klinefelter syndrome (KS), represents the most common form of sex chromosomal aneuploidy and affects approximately 1 in 650 newborn males [9, 10]. In 1942, H.F. Klinefelter et al. described 9 patients with a syndrome characterised by tall stature, gynecomastia, small firm testes, azoospermia, hyalinisation of the seminiferous tubules, elevated excretion of follicle-stimulating hormone (FSH), and hypogonadism [11]. In 1959 P.A. Jacobs and J.A. Strong demonstrated the presence of an extra X chromosome in the karyotype of KS patients [12]. About 90% of KS patients have the karyotype 47,XXY and 7% have mosaicism 46,XY/47XXY. In contrast, karyotypes with a higher number of X chromosomes are very rare and represent 3% [10].
Lastly, Jacobs syndrome (JS), or XYY syndrome, is an aneuploidy resulting from an additional copy of the Y chromosome to the normal XY pair in men [13]. The presence of an extra Y chromosome was first described by Sandberg et al. in 1961 [14] and Jacobs et al. in 1965 [15]. Aberration occurs in approximately 1 out of 1000 live male births. About 85% of cases with XYY are never diagnosed due to variability of mild phenotypes [16]. Diagnosis is often late, with a median age at diagnosis of 17 years [17].
Moreover, skeletal disorders are quite common in sex chromosome aberrations. This article was written in memo­ry of Prof. Jerzy Kosowicz. He was one of the world’s first investigators to describe characteristic changes in the skeletal system occurring in many endocrinopa­thies (e.g. Turner syndrome, Klinefelter syndrome, hyper­parathyroidism) [18-20]. The bone lesions that he discussed were repeatedly mentioned in Polish and foreign publications in the field of endocrinology, radiology, and orthopaedics. Accurate knowledge of X-ray changes has helped to clarify and improve the diagnostics in endocrine disorders and has enabled early diagnosis and treatment of these diseases.
Our systematic review aimed to assess whether the presence of specific bone symptoms in the craniofacial and limb regions indicates selected sex chromosome aberrations such as Turner syndrome, Klinefelter syndrome, and Jacobs syndrome.

MATERIAL AND METHODS

SEARCH STRATEGY AND DATA EXTRACTION

This systematic review was conducted up to 15th August 2021, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [21], using the MEDLINE/PubMed database. The search formulas combined in PubMed Advanced Search Builder included (Turner syndrome) AND ((skeletal*) OR (synostosis) OR (craniofacial*) OR (dental*) OR (growth*)), (Klinefelter syndrome) AND ((skeletal*) OR (synostosis) OR (craniofacial*) OR (dental*) OR (growth*)), and (XYY syndrome) AND ((skeletal*) OR (synostosis) OR (craniofacial*) OR (dental*) OR (growth*)). The results were filtered by article type (case reports), publication date (since 2000), and language (English). Additionally, relevant articles from Google Scholar were added.
Records were screened by the title, abstract, and full text by 2 independent investigators. Studies included in this review matched all the predefined criteria according to PICOS (“Population”, “Intervention”, “Comparison”, “Outcomes”, “Study design”) – Table 1. A detailed search flowchart is presented in Figure 1.

RESULTS

In this systematic review, 55 papers following the search criteria were included. Figure 1 shows the detailed selection strategy of the articles. The inclusion and exclusion criteria are presented in Table 1.
Case reports were described in 26 different countries, considering a total of 79 patients. Table 2 presents basic data by type of SCA.
Among the included cases, 34 patients with Turner syndrome, 34 with Klinefelter syndrome, and 11 with Jacobs syndrome were described. The TS group was dominated by patients with mosaicism, whereas the KS group was mainly patients with karyotype 49,XXXXY and the JS group with karyotype 47,XYY. Most of the articles described teenage patients. The majority of patients came from Asia, followed by Europe, as well as Americas and Africa. More than half of the patients had detailed reported radiographic findings in the craniofacial region and extremities.
Table 3 presents the numbers of selected bone symptoms in the craniofacial and limb regions found in patients from the included studies. In TS patients, irrespectively of the karyotype, gothic palate and skeletal class II (manifested as mandibular retrognathia) with occasional crossbite predominated in the craniofacial region, as well as cubitus valgus in limb deformities. Because the most abundant karyotypes in selected KS patients were 47,XXY and 49,XXXXY, dysmorphic features such as hyper­telorism, flat nasal bridge, and retracted midface associated with the presence of skeletal class III were most commonly observed. Limb abnormalities were most commonly presented by patients with karyotype 49,XXXXY and expressed as clinodactyly, radioulnar synostosis, and pes planus. JS patients rarely demonstrated specific skele­tal changes. Among the observed features, the presence of hypertelorism, micrognathia, or radioulnar synostosis could be found.
Moreover, Table 4 shows examples of additional skele­tal symptoms in the included cases. Most of the abnormalities were identified in the craniofacial bones, asso­ciated with significant malocclusion among the described patients. The other malformations involved both limbs with a slight predominance of the lower extremity.

DISCUSSION

Although patients with SCAs demonstrate a variety of phenotypes, including bone and dental lesions, the proper diagnosis seems to be limited. Endocrine societies rarely recommend routine skeletal and craniofacial radiological examination for the diagnosis and management of these patients [72, 73]. Dual-energy X-ray absorptiometry (DXA) is the only radiological method recommended for bone mineral density (BMD) assessment. Most of the signs of skeletal changes are recognised on clinical examination, and other tests serve only to supplement or confirm a previously made diagnosis. Additionally, some skeletal abnormalities do not need a detailed radiological evaluation because of the marginal impact on patients’ quality of life. In contrast, dental manifestations may require expanded radiographic diagnosis, especially in patients presenting with malocclusion. In order to accurately assess the skeletal or dental nature of the bite disorder in orthodontic patients, a cephalometric radiograph is necessary [74]. It is also crucial to remember the screening role of panoramic radiographs that allow detection of such dental anomalies as taurodontism. However, especially in paediatric patients, radiation exposure safety must be considered [75].

TURNER SYNDROME

The basis for the diagnosis of the TS is the result of the cytogenetic test. The gold standard for diagnosis is postnatal karyotyping [76]. The literature shows divergent information on the prevalence of karyotypes in TS, which can be explained by technological progress and increasingly sensitive diagnostic methods [77]. As it currently stands, classical karyotype and mosaicism among TS patients account for 40-50% and 28-40%, respectively [72]. Furthermore, 99% of 45,X foetuses abort spontaneously [78]. The remaining group consists of TS patients with revealed structural X-chromosome aberrations.
A growing number of patients are diagnosed with TS during prenatal examination – mainly based on ultrasonography results. It is also possible to perform a prenatal karyotype analysis using chorionic villus sampling (CVS) or amniocentesis (AC) [76]. Moreover, molecular methods, such as Southern blotting, polymerase chain reaction (PCR), fluorescent PCR genotyping, or restriction fragment length polymorphism (RFLP), are used to detect TS in neonates [5].
Turner’s syndrome demonstrates characteristic developmental defects or dysmorphic features that occur with different frequencies. In a newborn, TS may be suspected in the presence of so-called “stigmata”: congenital lym­phoedema of the hands and feet, extra folds of skin on the neck, high-arched palate or cleft palate, small mandible, nail dysplasia, low posterior hairline, broad chest with widely-spaced and hypoplastic nipples, and congenital hip dislocation [79]. A decelerated increase in body length is already observed in foetal life [76]. At birth, a lower weight (by approx. 500 g) and a shorter body length (by approx. 3 cm) are noticed [8]. However, this syndrome may be reco­gnised later, e.g. during the diagnosis of short stature or primary amenorrhoea [80]. Slower growth rate in childhood, lack of pubertal growth spurt, and delayed growth end (approx. 20-21 years old) are observed [8]. Furthermore, osteoporosis is found in most patients with TS, especially in patients not treated with growth hormone and cyclic oestrogen/progesterone [81, 82].
It is believed that the deficit in height and skeletal deformities are due to the haploinsufficiency of the distal region of Xp, including the short stature homeobox (SHOX) gene (Xp22.33) [8, 26, 76, 83]. Moreover, SHOX mutations are also associated with Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) [84]. LWD is manifested with a wide spectrum of phenotypes, including short-normal stature to severe short stature with no, mild, or severe Madelung deformity. Langer et al. defined the LWD-specific radiological features in the upper extremity, such as triangularisation of the distal radial epiphysis with shortening of the ulnar segment, pyramidalisation of the distal carpal row, shortening and bowing of the distal radius, and widening of the articular space between the distal parts of radius and ulna. The Madelung deformity is also thought to be caused by decreased oestrogen levels, due to its essential role in closing the epiphyseal cleft [85]. Moreover, Binder et al. asserted that Turner girls tended to have an abnormal trian­gularisation of the distal radial epiphysis [83].
In addition to the stigmata mentioned above, Turner syndrome has typical bone defects concerning the axial and appendicular skeleton. The most frequent bone symptoms comprise short fourth metacarpals, short neck, Made­lung deformity, or genu valgum. In radiolo­gical diagnostics, the so-called “Kosowicz sign” concerns lunate bone displacement, thus reducing the carpal angle below 118° in Turner patients [86]. Also, knee joints are characteristically changed – the tibial metaphysis has mushroom-like enlargement or peaked projection on its medial surface [86]. Additionally, girls with TS usually have distinctive craniofacial features, such as gothic palate, crossbite, retrognathia with microgenia, and trigonocephaly [74, 79]. Furthermore, based on radiographs of the skull, Rzymski and Kosowicz observed the following characteristic findings: increased angle of the skull base, smaller sella turcica, decreased dimensions of the mastoid processes, enlarged and thicker mandible (as in males), and excessive pneumatisation of paranasal sinuses [87]. In reference to our recent unpublished study, including 37 TS patients with radiographs of the cranium and both extremities, the characteristic symptoms of TS, i.e. shortening of the fourth and fifth metacarpals, positive carpal sign, and elongation of fibula, occur with a frequency of nearly 100%, regardless of the karyotype. However, it has not been possible to determine the skeletal signs that would be pathognomonic for a selected karyotype. Also, Czyzyk et al. [88] pointed out the diversity of phenotype and karyotype characteristic for TS patients. In contrast, in our systematic review of case reports published after 2000, a negligible proportion of patients had detailed radiological examinations of the limbs. The majority of available papers focused on descriptions of craniofacial abnormalities based on cephalometric radiographs.
In differential diagnosis, Noonan syndrome presenting similar clinical symptoms should be considered (e.g. short stature, webbed neck, cardiac and renal disorders). However, this condition can affect both males and females because it is not associated with X-chromosomal abnormality [89].

KLINEFELTER SYNDROME

According to National Danish Cytogenetic Registry Study, only about one-fourth of Klinefelter patients are dia­gnosed in their lifetime [90]. KS is very rarely recognised prior to puberty or adulthood due to variable phenotypes and clinical presentations, which are age related. In addition, Abramsky and Chapple estimated that less than 10% of expected cases were diagnosed by prenatal amniocentesis [91]. In children and adolescents, KS detection is based on typical features, such as underdeveloped genitalia, hypotonia, gynecomastia, or learning and behavioural problems due to mental retardation [10]. The diagnosis is usually made in adult men evaluated for infertility and hypogonadism [10, 92]. The diagnosis of KS should be confirmed by chromosome analysis on lymphocytes from peripheral blood [93, 94].
The number of the extra X chromosome is positively correlated with the severity of the KS phenotype. In patients with mosaicism (especially 46,XY/47,XXY), the clinical presentation is relatively mild, and bone radiolo­gical examination rarely shows abnormalities [95]. About half of KS boys manifest motor impairments associated with muscular hypotonia, articular hypermobility, pes planus, or genu valgum [10], as well as radioulnar synostosis or bilateral fifth finger clinodactyly [94]. Additionally, based on radiographs of the skull, Kosowicz and Rzymski observed the following characteristic findings: decreased angle of the skull base, shortening of the anterior cranial fossa, shorter mandibular rami, and deepening of the posterior cranial fossa [19]. Among dental conditions, inter alia cleft palate, malocclusion, and taurodontism occur in KS. Furthermore, tall stature is partially implicated in hypogonadism in decelerated closure of epiphyseal plates. Also, SHOX overexpression results in accelerated growth velocity [10]. The number of X chromosomes is negatively correlated with the height in KS patients [93]. Delayed treatment with testosterone could lead to lowered muscle and bone mass, resulting in osteoporosis and a higher prevalence of hip and spine fractures [10, 90]. In our systematic review, similarly to TS patients, most included case reports were focused on craniofacial features based on cephalometric analysis.
Klinefelter syndrome should be differentiated from other growth disturbances, such as Marfan syndrome [96], acromegaly [97], or fragile X syndrome (FXS) [98].

JACOBS SYNDROME

Currently, prenatal diagnosis is made using preferably cell-free foetal DNA instead of invasive amniocentesis [99-101]. Postnatally, JS is detected by karyotyping from the patient’s blood [91]. The main JS karyotype is 47,XYY, and other mosaics (e.g. 46,XY/47,XYY) are less common [17].
JS may be associated with mental disabilities, such as autism spectrum disorder (ASD) or attention deficit hyper­activity disorder (ADHD) [16]. It can also be related to behavioural problems (e.g. aggression, sociopathy) [102, 103]. JS patients are more predisposed to systemic disorders, including asthma, seizures, and tremors [16]. Also, males with JS are often fertile with normal external genitalia and can have healthy offspring [103].
The JS phenotypes could be expressed diversely. In JS patients, among the most common findings are tall stature, brachy- or clinodactyly, pes planus, and hypotonia. Radiologically, radioulnar synostoses can be observed [104]. Moreover, dental examination usually manifests as progenia with open bite, macrodontia, or taurodontism [16]. Hypertelorism is also a specific facial feature in JS. According to our systematic review, JS patients constituted a significant minority and manifest a diverse range of skeletal abnormalities.
The differential diagnosis of JS should include growth disorders, such as Marfan syndrome, Sotos syndrome, and Klinefelter syndrome [13].

STUDY LIMITATIONS

Our systematic review included only individual case reports that met the strict inclusion criteria. Therefore, the included patients may not reflect the actual occurrence of karyotypes in the given types of SCAs, because rarer and unique cases are more often published in reput­able journals. The described skeletal lesions may not represent the population of patients with SCAs, but the goal of this review was to collect bone manifestations published in the literature. The selection of only one medi­cal database (albeit the most popular) should be considered a study limitation. We know that there may be other non-included papers published in local journals not indexed in this database and written in languages other than English, which limits their availability.

CONCLUSIONS

Diagnosis and treatment of patients with SCAs require a multidisciplinary approach. Skeletal manifestations in the craniofacial and limb regions could help diagnose these reviewed sex chromosome aberrations. However, further observational studies on larger populations are advisable to determine the pathognomonic symptoms for selected genetic syndromes.

DISCLOSURE

The authors declare no conflict of interest.

REFERENCES