Deborah Wenkert

Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions.

Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.

Bisphosphonate‐Induced Osteopetrosis: Novel Bone Modeling Defects, Metaphyseal Osteopenia, and Osteosclerosis Fractures After Drug Exposure Ceases

In 2003, we reported on a 12‐yr‐old boy who had developed osteopetrosis (OPT) while receiving pamidronate (PMD) for idiopathic bone pain and enigmatic elevation in circulating bone alkaline phosphatase. Now 17 yr of age, he was re‐evaluated 6.5 yr after PMD exposure stopped. Our patient described less bone pain but further limb fractures. His growth plates were fused, yet hyperphosphatasemia persisted. Radiographs documented interval fractures of a metacarpal, an osteosclerotic distal radius, and a dense diaphyseal segment of an ulna where a “chalkstick” break remained incompletely healed after 2 yr. There was new L4 spondylolysis, and previous L5 spondylolysis had caused spondylolisthesis. Modeling disturbances of OPT persisted, but partial recovery was shown by metaphyseal surfaces with a unique concave shape. Metaphyseal osteosclerosis had remodeled imperfectly to become focal areas of dense, diaphyseal bone. Newer metaphyseal bone was unexpectedly osteopenic, especially in his distal femurs where cortices were thin and a paucity of trabeculae was documented by CT. Femoral necks had become short and wide with an abnormal contour. A “bone‐within‐bone” configuration was now present throughout his skeleton. In vertebrae, endplates were thin, and trabecular osteopenia was present central and peripheral to the bands of osteosclerosis. BMD Z‐scores assessed by DXA had decreased into the normal range in his spine, hip, and whole body. Iliac crest biopsy showed active bone formation, with much less accumulated primary spongiosa than during the PMD infusions. Osteoclasts that had been dysmorphic, round cells without polarization and off of bone surfaces were now unremarkable in number, location, and appearance. In conclusion, bisphosphonate toxicity during childhood can impair skeletal modeling and remodeling with structural changes that evolve and carry into adult life.

Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review)

Hypophosphatasia (HPP) is caused by deactivating mutation(s) within the gene that encodes the tissue‐nonspecific isoenzyme of alkaline phosphatase (TNSALP). Patients manifest rickets or osteomalacia and dental disease ranging from absence of skeletal mineralization in utero to only loss of adult dentition. Until recently, HPP skeletal disease in utero was thought to always predict a lethal outcome. However, several reports beginning in 1999 emphasized a benign prenatal form of HPP (BP‐HPP) where skeletal disease detected in utero had a mild postnatal course. Here we describe prenatal and postnatal findings of 17 additional BP‐HPP patients among our 178 pediatric HPP patients. Their findings are compared with those of their siblings with HPP, carrier parents, and others with identical TNSALP mutations. New information concerning 7 previously published BP‐HPP patients accompanies a review of the HPP literature. Among our 17 BP‐HPP patients, prenatal ultrasound showed normal chest or abdominal circumferences where recorded. Sometimes, poor skeletal mineralization, fetal crowding, and third‐trimester improvement were observed. Postnatally, extremity bowing further improved (13 patients). BP‐HPP severity postnatally spanned the “infantile” to “odonto” HPP phenotypes, resembling our patients who harbored identical TNSALP mutation(s). Eight had autosomal dominant (AD) and 9 had autosomal recessive (AR) BP‐HPP. Fourteen of our 15 mothers were HPP carriers or affected. Of the 41 cumulative BP‐HPP patients (24 literature cases meriting a BP‐HPP diagnosis since 1996 plus our 17 patients), 63% had AR BP‐HPP. Maternally transmitted HPP involved 11 of the 13 total AD BP‐HPP probands (p = 0.01), supporting a maternal in utero effect on the baby. Fetal crowding, normal fetal mineralization and chest size, and TNSALP heterozygosity seem to identify BP‐HPP. However, bowed fetal long bones with AR HPP, specific TNSALP mutations, or poor skeletal mineralization before the third trimester do not reliably diagnose HPP lethality.

Deactivating Germline Mutations in LEMD3 Cause Osteopoikilosis and Buschke-Ollendorff Syndrome, but Not Sporadic Melorheostosis

Autosomal dominant OPK and BOS feature widespread foci of osteosclerotic trabeculae without or with skin lesions, respectively. Occasionally, a larger area of dense bone in OPK or BOS resembles MEL, a sporadic sclerosing disorder primarily involving cortical bone. Others, finding deactivating germline LEMD3 mutations in OPK or BOS, concluded such defects explain all three conditions. We found germline LEMD3 mutations in OPK and BOS but not in sporadic MEL.

Chronic Recurrent Multifocal Osteomyelitis Mimicked in Childhood Hypophosphatasia

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by low serum alkaline phosphatase (ALP) activity caused by inactivating mutations within TNSALP, the gene that encodes the “tissue‐nonspecific” isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate, inhibits hydroxyapatite crystal growth leading to rickets or osteomalacia. Chronic recurrent multifocal osteomyelitis (CRMO) is the pediatric syndrome of periarticular pain and radiographic changes resembling infectious osteomyelitis but without lesional pathogens. Some consider CRMO to be an autoinflammatory disease. An unrelated boy and girl with the childhood form of HPP suffered chronic, multifocal, periarticular pain, and soft tissue swelling. To investigate this unusual complication, we evaluated their cumulative clinical, biochemical, radiological, and histopathological findings and performed mutation analysis of their TNSALP alleles. The earliest radiographic disturbances were typical of childhood HPP. Subsequently, changes consistent with CRMO developed at sites where there was pain, including lucencies, osteosclerosis, and marked expansion of the underlying metaphyses. Bone marrow edema was shown by MRI. Biopsies of affected bone showed nonspecific histopathological findings and no pathogens. The boy was heterozygous (c.1133A>T, p.D378V) and the girl compound heterozygous (c.350A>G, p.Y117C, c.400_401AC>CA, p.T134H) for different TNSALP missense mutations. Nonsteroidal anti‐inflammatory drugs diminished their pain, which improved or resolved at maturity. HPP should be considered when CRMO is a diagnostic possibility. Metaphyseal radiographic changes and marrow edema associated with periarticular bone pain and soft tissue swelling suggestive of osteomyelitis can complicate childhood HPP.

Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis?

Epidermal nevus syndrome (ENS) is a rare, sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype that can include focal or generalized skeletal disease. We describe a young man with ENS manifesting right‐sided linear skin lesions, generalized weakness, diffuse osteopenia associated with hypophosphatemic rickets, and distinctive focal bone lesions ipsilateral to the skin findings. Review of the literature concerning ENS–associated skeletal disease suggested such focal bone defects are fibrous dysplasia, but our patient did not have the typical radiographic or histopathologic findings of fibrous dysplasia. Nevertheless, his circulating fibroblast growth factor 23 (FGF‐23) level was elevated, likely functioning as a “phosphatonin,” yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune–Albright syndrome were detected in his leukocytes or affected skin. We postulate that the focal skeletal disease, although different than fibrous dysplasia, may be a source of FGF‐23 in ENS.

Camurati‐engelmann disease: Unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand

We report a 32‐year‐old man and his 59‐year‐old mother with a unique and extensive variant of Camurati‐Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock‐knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z‐scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25‐hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin‐like growth factor (IGF)‐1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5′11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12‐bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency‐associated‐peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity.

Elevated Serum Lactate Dehydrogenase Isoenzymes and Aspartate Transaminase Distinguish Albers-Schönberg Disease (Chloride Channel 7 Deficiency Osteopetrosis) Among the Sclerosing Bone Disorders

Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss‐of‐function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB‐CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss‐of‐function mutation in CLCN7 [Albers‐Schönberg disease (A‐SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age‐appropriate controls, were persistent and essentially concordant in A‐SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A‐SD. LDH isoenzyme quantitation showed excesses of LDH‐2, ‐3, and ‐4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate‐induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP‐5b and BB‐CK also were markedly elevated in A‐SD. Hence, high serum levels of several enzymes characterize A‐SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.

Fibrodysplasia ossificans progressiva: middle-age onset of heterotopic ossification from a unique missense mutation (c.974G>C, p.G325A) in ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is the rare mendelian disease characterized by congenital malformation of the great toes preceding heterotopic ossification (HO) and caused by heterozygous activating mutation of the ACVR1 gene, which encodes the ALK2 receptor for bone morphogenetic proteins. Early adult life is the latest reported presentation for the HO of FOP. The patient of our report first developed HO from FOP at 47 years of age. She had congenital hallux valgus deformity but despite various traumas was previously well. HO began several months after a brief, seemingly viral, illness. Sudden and progressive pain, redness, warmth, and swelling appeared over a scapula. Computed tomography was remarkable for asymmetrical thickening of muscles and fascial planes. At first, the significance of the great toe abnormalities went unrecognized elsewhere, and biopsy for suspected inflammatory fasciitis revealed proliferating fibroblasts with scattered inflammatory cells. Prednisone improved her symptoms but, when tapered, swellings developed on her chest, posterior thorax, and flank, and FOP was diagnosed. Methylprednisolone, methotrexate, and alendronate seemed to help her symptoms, but the lesions worsened and HO appeared and rapidly progressed. Mutation analysis of the ACVR1 gene revealed heterozygosity for a unique missense defect (c.974G > C, p.G325A) that predicted a conservative (mild) amino acid change within the kinase domain of ALK2. Hence, HO in FOP can be delayed until middle‐age, and perhaps provoked by a viral illness. Nevertheless, progression of HO can then be rapid despite bisphosphonate and high‐dose immunosuppressive therapy. Possibly, our patients late‐onset HO reflects her mild alteration of ALK2 or some protective and therapeutically useful genetic, epigenetic, or nongenetic factor. Recognition of presymptomatic individuals or late‐onset HO in FOP should have these patients avoid traumas, treatments, and maybe viral illnesses that can initiate or exacerbate the HO. If the diagnosis of FOP is unclear, ACVR1 mutation analysis is available at certified laboratories.

Dysosteosclerosis Presents as an “Osteoclast-Poor” Form of Osteopetrosis: Comprehensive Investigation of a 3-Year-Old Girl and Literature Review

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.