Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66-year-old man

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22 . Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the pro-gression of SEMDJL2 throughout the life of the oldest individual reported in the literature — a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.

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).

| CASE REPORT
The 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 (À4 SD). Hand and middle finger lengths were on the 5th centile ( Figure 2a); foot length was short (À4SD; 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 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.
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 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. 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 STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.