Chondrodysplasia, enchondromas and a chest deformity causing severe pulmonary morbidity in a boy with a PTHLH duplication: A case report

Abstract

Parathyroid hormone-like hormone (PTHLH) plays an important role in bone formation. Several skeletal dysplasias have been described that are associated with disruption of PTHLH functioning. Here we report on a new patient with a 898 Kb duplication on chromosome 12p11.22 including the PTHLH gene. The boy has multiple skeletal abnormalities including chondrodysplasia, lesions radiographically resembling enchondromas and posterior rib deformities leading to a severe chest deformity. Severe pulmonary symptoms were thought to be caused by limited mobility and secondary sputum evacuation problems due to the chest deformity. Imaging studies during follow-up revealed progression of the number of skeletal lesions over time. This case extends the phenotypic spectrum associated with copy number variation of PTHLH.

Keywords: AP, anteroposterior; CT, computed tomography; Chondrodysplasia; DEXA, dual-energy X-ray absorptiometry; Enchondroma; IHH, Indian hedgehog; PA, posteroanterior; PTHLH; PTHLH, parathyroid hormone-like hormone; PTHrP, parathyroid hormone related peptide; Parathyroid hormone-like hormone; SDS, standard deviation score.

Fig. 1

A small and deformed chest in a boy with a PTHLH duplication at presentation (almost two years old) and during follow-up (at the age of six years).

Fig. 2

Radiographs made as part of the diagnostic work-up at presentation. A, B, C. Anteroposterior (AP) and lateral radiograph of the right (two radiopaque markers) and AP left elbow. The radiograph of the right elbow was initially interpreted as a fracture of the proximal radius. The radius shows a metaphyseal well-demarcated lucency with local angulation. The AP radiographs shows sclerotic margins of the lesion. The lateral side of the metaphysis of the left radius shows a cortical irregularity and slight bowing. D. Slightly oblique AP chest radiograph shows the deformity of the chest with slender down slanted ribs. E, F. AP radiographs of the ankles shows symmetrical metaphyseal cortical irregularity of the medial side of the fibulas. G, H, I. Normal development of the thoracolumbar spine and skull. J, K. Posteroanterior (PA) radiograph of both hands, there is some sclerosis at the base of the fourth metacarpal of the right hand (arrow). The tuft of the second digit of the right hand is irregular (insert). L. AP pelvis, note the linear irregularities on the inside of the iliac bones. There is slight flaring of the iliac bones and mild dysplasia of the hips.

Fig. 3

Genomic locus of the duplication region on chromosome 12p11. The duplication is outlined in the red box, containing 9 genes including PTHLH highlighted in blue. The other OMIM genes within this region are STK38L, ARNTL2, PPFIBP1, REP15, MRPS35 and KLHL42.

Fig. 4

Radiologic findings at presentation and during follow-up. Upper row: Chest development at presentation (1 years 4 months) and during follow-up (3 years 5 months and 4 years 6 months). The chest radiographs shows relatively short down slanted ribs with proximal sclerotic irregularities with at multiple levels interruption of the ribs posteriorly. Over time the chest narrows. Also note the irregular aspect of the medial claviculae. Second row: AP pelvic radiograph at presentation, and 25 and 38 months after first presentation. Note the irregular and dysplastic acetabular development. The irregularities on the inside of the pelvic ring have normalized over time. Note growth resumption lines in the iliac bones and proximal femora as a result of bisphosphonate treatment. Third and fourth row: Radiographs of both ankles at presentation and during follow-up to age 7 years. Imaging shows the development of bilateral symmetric anomalies radiographically resembling enchondromas. As a result of growth the lesions ‘move away’ from the growth plate. Over time the lesions develop into a ‘pseudo-arthrosis’. Note growth resumption lines in the distal tibia and fibula as a result of bisphosphonate treatment. Fifth row: AP radiographs of the feet at presentation and during 5 years of follow-up. Figures show an irregular ossification of the tuft of the first digit of the left foot, irregular ossification of the distal metaphysis of the fifth digit of the right foot, and a well demarcated lucency at the base of the third metatarsal of the right foot. The fifth metatarsal of the right foot shows an irregular distal metaphysis and significant shortening.

Fig. 5

A. CT of the chest (axial oblique reconstruction) 57 months after initial presentation, shows an anomalous development of the proximal part of the ribs with a strong curvature and bilateral ‘pseudoarthrosis’ of the ribs at multiple levels. Due to the posterior anomaly the ribs are relatively short. B. On CT, 32 months after first presentation extreme thinning of the iliac bones at the level of the sacroiliac joint is visible.