Dysosteosclerosis presents as an "osteoclast-poor" form of osteopetrosis: comprehensive investigation of a 3-year-old girl and literature review

Abstract

Dysosteosclerosis (DSS), an extremely rare dense bone disease, features short stature and fractures and sometimes optic atrophy, cranial nerve palsy, developmental delay, and failure of tooth eruption in infancy or early childhood consistent with osteopetrosis (OPT). Bone histology during childhood shows unresorbed primary spongiosa from deficient osteoclast action. Additionally, there is remarkable progressive flattening of all vertebrae and, by adolescence, paradoxical metaphyseal osteopenia with thin cortical bone. Reports of consanguinity indicate autosomal recessive inheritance, yet more affected males than females suggest X-linked recessive inheritance. We investigated a nonconsanguineous girl with DSS. Osteosclerosis was discovered at age 7 months. Our studies, spanning ages 11 to 44 months, showed weight at approximately 50th percentile, and length diminishing from approximately 30th percentile to -2.3 SD. Head circumference was +4 SD. The patient had frontal bossing, blue sclera, normal teeth, genu valgum, and unremarkable joints. Radiographs showed orbital and facial sclerosis, basilar thickening, bone-in-bone appearance of the pelvis, sclerotic long bone ends, and fractures of ribs and extremities. Progressive metaphyseal widening occurred as vertebrae changed from ovoid to flattened and became beaked anteriorly. A hemogram was normal. Consistent with OPT, serum parathyroid hormone (PTH) concentrations reflected dietary calcium levels. Serum bone alkaline phosphatase, osteocalcin, and TRACP-5b were subnormal. The iliac crest contained excessive primary spongiosa and no osteoclasts. No mutations were identified in the splice sites or exons for the genes encoding chloride channel 7, T-cell immune regulator 1, OPT-associated transmembrane protein 1, and monocyte colony-stimulating factor (M-CSF) and its receptor C-FMS, ANKH, OPG, RANK, and RANKL. Genomic copy-number microarray was unrevealing. Hence, DSS is a distinctive OPT of unknown etiology featuring osteoclast deficiency during early childhood. How osteopenia follows is an enigma of human skeletal pathobiology.

Fig. 1

Patient. (A) At age 44 months, there is frontal bossing, a small midface, low-set ears, and blue sclerae. (B) At age 3 years, the recurring dermatosis (arrow) is present on the lower abdomen.

Fig. 2

Skull. (A) At age 22 months, anteroposterior view of the skull shows sclerosis that affects the periorbital region and skull base. The sinuses are opacified. (B) At age 33 months, the neurocranium appears large on lateral view, with diffuse sclerosis greatest at the base. The midface is small, and the mandibular angle is obtuse.

Fig. 3

Spine. This anteroposterior projection (A) at 22 months shows sclerotic vertebrae, dense ribs with healing fractures, sclerotic medial clavicles, and bone-in-bone appearance in the ilium as seen in some forms of OPT. Between 7 (B) and 33 (C) months of age, the lateral spine shows sclerosis and flattening of vertebral bodies that increased with age. The vertebral bodies have a pointed configuration anteriorly (greatest at 7 months). Sclerosis affects the entire vertebra.

Fig. 4

Appendicular skeleton. At 22 (A) and 33 (B) months of age the lower extremities, and at 7 (C) and 33 (D) months of age the left upper extremity, show sclerosis greatest at the proximal and distal ends of the bones and metaphyseal expansion from tubulation failure greatest in the distal femurs. (E) There are transverse metaphyseal bands of osteosclerosis, as seen in some forms of OPT (arrows). A healing fracture featuring focal bone expansion and periosteal new bone formation is present in the distal left femur at the junction of the sclerotic and nonsclerotic bone (arrows) (A). There is a slight irregularity of the physeal plates and adjacent provisional zones of calcification (C, D, E). Sclerosis in the upper extremities has increased at the ends of the bones between 7 (C) and 33 (D) months of age. In the leg bones and distal right femur, the junction between the sclerotic and nonsclerotic bone is sharp, but not well defined in the proximal femurs or distal left femur. The junction between the sclerotic and nonsclerotic bone can have a transverse or oblique shape.

Fig. 5

Hand and foot radiographs. At 22 (A) and 33 (B) months of age the left hand and at 22 (C) months of age the left foot show diffuse sclerosis greatest in the metaphyses of the metacarpals and metatarsals and distal radius and ulna. The amount of sclerosis in the proximal phalanges varies from much to little and is greatest in the metaphyseal regions. The tarsals have some sclerosis greatest in the cuboids. Pathologic fractures are shown through sclerotic bone in the distal radius (arrow) and ulna in the anteroposterior projection (D) at 30 months and near nonsclerotic bone in the right femur (arrows) at 47 months (E).

Fig. 6

Osteoclast-poor osteopetrosis. Sections of the nondecalcified transapophyseal iliac crest biopsy at age 25 months show a growth plate (A) containing proliferative (Pr) and hypertrophic (Hy) chondrocytes that lack the normal columnar orientation along the axis perpendicular to the bone surface. In this toluidine-stained section, the bone surface is toward the left, and the chondrocytes should be arranged in rows from left to right. Scale bar = 200 µm. H&E-stained (B) and toluidine blue–stained (C) sections demonstrate disorganized trabeculae composed primarily of cartilage (purple in both stains), with only minimal bone matrix (pink in B, pale gray in C). A von Kossa stain (D) shows that the cartilage in these “trabecular” areas is calcified. TRAP staining (E) fails to identify any osteoclasts. Scale bar (B–E) = 100 µm.