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/lp/wiley/spondyloepimetaphyseal-dysplasia-with-joint-laxity-type-2-aggregating-7dir8cIY2d
- Publisher
- Wiley
- Copyright
- © 2023 Wiley Periodicals LLC.
- ISSN
- 1552-4841
- eISSN
- 1552-485X
- DOI
- 10.1002/ajmg.c.32053
- Publisher site
- See Article on Publisher Site
Abstract
INTRODUCTIONSpondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2; MIM:603546)—also, SEMDJL Hall or leptodactylic type—is demarcated by the presence of generalized joint laxity, knee malalignment, slender hands, and short stature (Boyden et al., 2011; Hall et al., 1998, 2002; Min et al., 2011; Tüysüz et al., 2015). Radiological hallmarks include platyspondyly, slender metacarpals and metatarsals, metaphyseal vertical striations and irregularities, and progressive epiphyseal dysplasia with misaligned joints progressing into precocious osteoarthritis (Hall et al., 1998, 2002; Holder‐Espinasse et al., 2004; Kim et al., 2009; Sulko & Kozlowski, 2008). Due to weakened cartilage in the airway tract, tracheolaryngomalacia may arise in neonates, and may be followed by recurrent respiratory tract infections (Boyden et al., 2011; Park et al., 2007; Tüysüz et al., 2015).Heterozygous pathogenic variants in the Kinesin Family Member 22 gene (KIF22, 16p11; MIM:603213) confers SEMDJL2 through autosomal dominant inheritance (Boyden et al., 2011; Min et al., 2011). KIF22 mRNA is expressed in bone, cartilage, joint capsule, ligament, and skin (Fagerberg et al., 2014), and recent results suggest that KIF22 is essential for the transition between metaphase and anaphase (Thompson et al., 2022). Pathogenic variants of KIF22 result in chromosomal recongression during anaphase, leading to incomplete cellular division (Thompson et al., 2022). SEMDJL2‐pathogenic variants in KIF22 typically result from changes in two codons in a genetic hotspot (c.442C > T, p.Pro148Ser; c.443C > T, p.Pro148Leu; c.446G > A, p.Arg149Gln; c.446G > T, p.Arg149Leu) (Boyden et al., 2011). Herein, we report on the oldest reported patient in the literature with SEMDJL2, a 66‐year‐old man (Figure 1) with a pathogenic variant of KIF22 (c.443C > T, p.Pro148Leu). Within this report, the chronicle of radiological findings (years 20, 34, 40, and 45) are consistent with the most recent (year 65) radiographs (Figure 2).1FIGUREPictures of the patient age 45 (left) and 65 (right).2FIGURERadiographs of the SEMDJL2‐proband, age 65. (a) Anterior–posterior (AP) view of the right hand reveals subluxation of the second metacarpals (MC). There is flexion contracture in the fifth distal interphalangeal (DIP) joint. Significant degenerative changes are seen in the first and fifth carpal‐metacarpal (CMC) joint with milder changes involving all MC joints. The carpal bones are small, and the proximal phalanges and metacarpals are slender. There are metaphyseal irregularities of the distal radius and ulna. (b, c) The vertebral bodies show concavity of the endplates. There are tiny osteophytes in the thoracic and lumbar spine. (d) The architecture of the tarsal bones is distorted; the bones appear flattened. The metatarsals are slender. The distal interphalangeal joints of the second and fourth toes are maintained in flexed position. (e) Right leg. There is anterior bowing at the proximal metaphysis of the tibia consistent with metaphyseal irregularities. (f) There are severe degenerative changes in all aspects of the elbow joint, with associated deformity. (g) Posterior–anterior (PA) view of the chest. There is moderate dorsal scoliosis. The humeral heads are close to the acromions and there are degenerative change at the acromioclavicular joints. (h) AP view of the hips. The femoral heads appear small and deformed. The femoral neck is short.CASE REPORTThe proband was an uncomplicated term delivery following a normal pregnancy to non‐consanguineous parents (Mother: 29 years; Father: 44 years) and a sibship of 5. No abnormalities were initially noted at birth and length was not recorded. At 6 months, he received a tracheostomy in response to severe laryngomalacia. Due to recurrent pneumonia, he required multiple courses of antibiotics until the age of 5 years. Respiratory problems persisted until year 8, whereupon the tracheostomy tube was removed. Braces were fitted at the age of 2 years to assist walking which was compromised due to extreme lateral laxity of the knees. At age 3, short stature was noted. The proband developed mild scoliosis in the upper thoracic region, and joint instability—particularly in the knees and elbows. He did not experience joint dislocation or fracture.At age 20, the proband underwent a knee arthroscopy, where cruciate and lateral ligamentous instability were reported. The medial compartment had extensive intra‐articulus synovial proliferation with pannus formation and multiple loose bodies in the joint. Similar qualities were present in the elbow joint which limited elbow extension to 35° (Figure 2f). At age 25, his teeth were removed due to softening and yellowing. He was also identified with an enlarged prostate causing a poor urine stream. At this time, despite the difficulties imposed by SEMDJL2, the proband successfully ran a print shop.At 34, the proband's reported height was 149 cm (−4 SD). Hand and middle finger lengths were on the 5th centile (Figure 2a); foot length was short (−4SD; Figure 2d). He was noted to have mesomelic limb shortening. When standing, lumbar lordosis was apparent, and the chest was barrel shaped. His neck was short. Facially, supraorbital ridges, mild malar hypoplasia, a pronounced jaw, a broad nasal bridge, and an upturned nose with a broad base were observable. His feet lacked an arch, and the 4th and 5th toes exhibited clinodactyly. A reduction in joint movement was noted at the hips and shoulders. Arthritic changes were present in the hip and knee joints. In addition to generalized osteopenia, the following radiological changes were noted:Pelvis and Lower Limbs: The sacral ala was hypoplastic consistent with a narrow pelvic inlet (Figure 2h). The femoral heads were hypoplastic with a typical circular contour; the femoral necks were short (Figure 2h), and the femoral shafts were bowed laterally. As well, distal femoral epiphyses were hypoplastic and articular surfaces were irregular (Figure 2h). Proximal tibial epiphyses were hypoplastic and concave (Figure 2e). Tibial and fibular shafts were bilaterally narrow with mild hypoplasia at the distal epiphyses; the left tibia and fibula had mild medial bowing (Figure 2e). Tarsal bones were hypoplastic and deformed (Figure 2d). Metatarsals were slender and variable in lengths (Figure 2d). The distal‐interphalangeal joints of the right foot were deformed with valgus angulation in the 4th and 5th distal phalanges (Figure 2d).Spine and skull: Superior and inferior end plates of the lumbar spine had accentuated concavity and sclerosis of the borders (Figure 2b,c). Disc spaces were widened, notably in the central aspects. Posterior cortices in the lower lumbar vertebrae were concave; the anterior cortices of lumbar vertebrae were normal (Figure 2b,c). The mid thoracic spine was scoliotic to the right. In the cervical spine, atlanto‐occipital fusion and platybasia were observed. The inferior end plates of cervical vertebrae were markedly concave, causing posterior disc space widening.Upper limbs: Bilateral clinodactyly was present (Figure 2a). The carpal bones were hypoplastic and the metacarpals were slender. The third 3rd and 4th metacarpals were short relative to the normal length of the 5th metacarpal (Figure 2a).At age 40, his knee joint changes significantly limited mobility. Moreover, progressive joint constraints, like elbow contractures, shoulder limitation, a lack of wrist rotation, and reduced hip mobility began to impede his ability to maintain personal hygiene and complete daily tasks. At age 45 (Figure 1), the proband retired due to worsening mobility derived from progressive joint stricture particularly derived from arthritic knees. At this time, he returned to the clinic for further examination of his declining mobility. His radiographs again demonstrated generalized osteopenia.The spine was markedly abnormal with cod‐shaped vertebral bodies, degenerative disc disease through osteophyte formation at C5‐6 and C6‐7. Ribs T9‐T12 were abnormal in shape with a “coat‐hanger” deformity. Advanced osteoarthritic changes were identified in the acromioclavicular and elbow joints (Figure 2f,g). In his late 40s, the proband developed obstructive sleep apnea but elected against using CPAP. He also developed ankle angle lock, hearing loss (right ear), Bells' palsy, ischemic cardiomyopathy, and congestive heart failure.At age 65 (Figure 1), the proband moved into a senior home, due to continued joint contracture causing immobility and inability to care for personal hygiene. With this lifestyle change, he was reappraised in the genetic clinic at which time confirmatory genetic testing was performed and a diagnosis of SEMDJL2 was confirmed. At this time, his height had further decreased to 138 cm.DISCUSSIONThe proband's clinical findings are consistent with 29 previously reported cases of SEMDJL2 (Table S1). The proband presented with core characteristics such as short stature (29/29), midface hypoplasia (26/29), nasal bridge deformity (17/18), joint laxity (29/29), slender hands (25/25), knee malalignment (25/26) and normal intelligence (18/20). Furthermore, the proband presented with other characteristics, including macrocephaly (7/9), frontal bossing (8/9), short neck (8/9), tracheolaryngomalacia (9/15), laryngeal stenosis (6/7), and recurrent respiratory infections (5/6).Similarly, the proband's radiological presentation is consistent with other reported cases of SEMDJL2 given the presence of slender and tapered femoral necks (24/24), small and irregular epiphyses (24/24), scoliosis (18/25), vertebral end‐plate irregularities (16/19), slender metacarpals (24/24), small and irregular carpal bones (22/22), and delayed carpal bone age (24/24). Unfortunately, metaphyseal characteristics—two core radiological findings of SEMDJL2 (24/24)—were not documented in the radiological report, however, the proband's X‐rays suggest that they are present (Figure 2a,e). As with the clinical findings, radiological findings demonstrated additional characteristics, such as small/irregular tarsal bones (6/6), slender metatarsals (11/11), clinodactyly (4/5), lumbar lordosis (5/6), and platyspondyly (8/16).Beyond these core characteristics, several clinical findings are atypical. A key development is the loss of joint mobility throughout his life, beginning with knee and elbow stricture (year 20) and eventually limitation of the shoulders, hips, ankles, and wrists (year 40). Although other articles report limitation of the elbows (Hall et al., 2002; Mégarbané et al., 2003; Nishimura et al., 2003; Park et al., 2007; Rossi et al., 2005; Tüysüz et al., 2015), hips (Hall et al., 2002), shoulders (Park et al., 2007), and digits (Rossi et al., 2005), our proband stands as an outlier; no previous reports relay the progressive development of body‐wide joint limitation in a SEMDJL2 patient.As well, the proband experienced several notable developments throughout his life, namely, prostatic enlargement (year 25), edentulism (year 25), and congestive heart failure (>year 45).The proband's benign prostatic hyperplasia (year 25) is interesting as this complication typically presents in older men (>50 years) (National Institute, of Diabetes, & Kidney Diseases (US), 1998). Whether his BPH resulted from SEMDJL2 remains unclear. Evidence suggests that prostate cells may express KIF22 (Fagerberg et al., 2014), however, the sample size (n = 4) is small and the data regarding KIF22's presence in prostate cells is not robust. Regarding the proband's edentulism and congestive heart failure: the proband lived in an area with fluoridated water. In his clinical reappraisal at age 36, the proband spoke about his chronic use of tobacco—that is, smoking half‐a‐pack per day. The proband's edentulism (Krall et al., 1997) and congestive heart failure (Aune et al., 2019) may have resulted from chronic cigarette use, rather than SEMDJL2. Moreover, a review found that edentulous patients had a higher risk of coronary artery plaque formation (2.32x) relative to non‐edentulous patients (Felton, 2009). It follows that the proband's edentulism may have contributed to his ischemic cardiomyopathy and congestive heart failure.Despite the proband's challenges with SEMDJL2, he has lived a fruitful life: he graduated high school with above average grades, started his own business, and earned his pilot's private license in his early 40s. Unfortunately, at age 45, the proband lost his ability to walk due to arthritis in his knees. At 65, he lost the ability to care for his personal hygiene due to body‐wide joint limitation. Therein, he moved to a seniors' lodge, where he receives the help that he needs.In conclusion, we present the oldest reported individual affected by SEMDJL2 to illustrate potential complications that can occur through life. Nevertheless, it is important to remember that intellect is unaffected and individuals that live with SEMDJL2 can lead productive and fulfilling lives.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no new data were created or analyzed in this study.REFERENCESAune, D., Schlesinger, S., Norat, T., & Riboli, E. (2019). Tobacco smoking and the risk of heart failure: A systematic review and meta‐analysis of prospective studies. European Journal of Preventive Cardiology, 26(3), 279–288.Boyden, E. D., Campos‐Xavier, A. B., Kalamajski, S., Cameron, T. L., Suarez, P., Tanackovich, G., … Bonafé, L. (2011). Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. The American Journal of Human Genetics, 89(6), 767–772.Fagerberg, L., Hallström, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., … Uhlén, M. (2014). Analysis of the human tissue‐specific expression by genome‐wide integration of transcriptomics and antibody‐based proteomics. Molecular & Cellular Proteomics, 13(2), 397–406.Felton, D. A. (2009). Edentulism and comorbid factors. Journal of Prosthodontics: Implant, Esthetic and Reconstructive Dentistry, 18(2), 88–96.Hall, C. M., Elcioglu, N. H., MacDermot, K. D., Offiah, A. C., & Winter, R. M. (2002). Spondyloepimetaphyseal dysplasia with multiple dislocations (Hall type): Three further cases and evidence of autosomal dominant inheritance. Journal of Medical Genetics, 39(9), 666–670.Hall, C. M., Elcioglu, N. H., & Shaw, D. G. (1998). A distinct form of spondyloepimetaphyseal dysplasia with multiple dislocations. Journal of Medical Genetics, 35(7), 566–572.Holder‐Espinasse, M., Fayoux, P., Morillon, S., Fourier, C., Dieux‐Coeslier, A., Manouvrier‐Hanu, S., … Hall, C. M. (2004). Spondyloepimetaphyseal dysplasia (Hall type) with laryngeal stenosis: A new diagnostic feature? Clinical Dysmorphology, 13(3), 133–135.Kim, O. H., Cho, T. J., Song, H. R., Chung, C. Y., Miyagawa, S. I., Nishimura, G., … Unger, S. (2009). A distinct form of spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL)‐leptodactylic type: Radiological characteristics in seven new patients. Skeletal Radiology, 38(8), 803–811.Krall, E. A., Dawson‐Hughes, B., Garvey, A. J., & Garcia, R. I. (1997). Smoking, smoking cessation, and tooth loss. Journal of Dental Research, 76(10), 1653–1659.Mégarbané, A., Ghanem, I., & Le Merrer, M. (2003). Spondyloepimetaphyseal dysplasia with multiple dislocations, leptodactylic type: Report of a new patient and review of the literature. American Journal of Medical Genetics Part A, 122(3), 252–256.Min, B. J., Kim, N., Chung, T., Kim, O. H., Nishimura, G., Chung, C. Y., … Cho, T. J. (2011). Whole‐exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. The American Journal of Human Genetics, 89(6), 760–766.National Institute, of Diabetes, & Kidney Diseases (US). (1998). Prostate enlargement: Benign prostatic hyperplasia (Vol. 98). National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.Nishimura, G., Honma, T., Shiihara, T., Manabe, N., Nakajima, E., Adachi, M., … Ikegawa, S. (2003). Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form: Clinical course and phenotypic variations in four patients. American Journal of Medical Genetics Part A, 117(2), 147–153.Park, S. M., Hall, C. M., Gray, R., & Firth, H. V. (2007). Persistent upper airway obstruction is a diagnostic feature of spondyloepimetaphyseal dysplasia with multiple dislocations (Hall type) with further evidence for dominant inheritance. American Journal of Medical Genetics Part A, 143(17), 2024–2028.Rossi, M., De Brasi, D., Hall, C. M., Battagliese, A., Melis, D., Sebastio, G., & Andria, G. (2005). A new familial case of spondylo‐epi‐metaphyseal dysplasia with multiple dislocations Hall type (leptodactylic form). Clinical Dysmorphology, 14(1), 13–18.Sulko, J., & Kozlowski, K. (2008). Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic or Hall type: Report of a case with normal face and literature review. Journal of Pediatric Orthopaedics, Part B, 17(6), 323–327.Thompson, A. F., Blackburn, P. R., Arons, N. S., Stevens, S. N., Babovic‐Vuksanovic, D., Lian, J. B., … Stumpff, J. (2022). Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation. eLife, 11, e78653.Tüysüz, B., Yılmaz, S., Erener‐Ercan, T., Bilguvar, K., & Günel, M. (2015). Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type: Longitudinal observation of radiographic findings in a child heterozygous for a KIF22 mutation. Pediatric Radiology, 45(5), 771–776.
Journal
American Journal of Medical Genetics Part B – Wiley
Published: Jun 1, 2023
Keywords: joint laxity; midface hypoplasia; SEMDJL2; short stature; spondyloepimetaphyseal dysplasia