Sanna Toiviainen-Salo

Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome

Shwachman‐Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone marrow failure, often associated with neurodevelopmental and skeletal abnormalities. Mutations in the SBDS gene have been shown to cause SDS. The purpose of this document is to provide draft guidelines for diagnosis, evaluation of organ and system abnormalities, and treatment of hematologic, pancreatic, dietary, dental, skeletal, and neurodevelopmental complications. New recommendations regarding diagnosis and management are presented, reflecting advances in understanding the genetic basis and clinical manifestations of the disease based on the consensus of experienced clinicians from Canada, Europe, and the United States. Whenever possible, evidence‐based conclusions are made, but as with other rare diseases, the data on SDS are often anecdotal. The authors welcome comments from readers.

Low density lipoprotein receptor‐related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia

Objective  Mutations in the low‐density lipoprotein receptor‐related protein 5 gene (LRP5) underlie osteoporosis–pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans.

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

Aromatase inhibitors (AIs), blockers of estrogen biosynthesis, delay bone maturation and therefore are used increasingly to promote growth in children and adolescents with growth disorders. The effects of treatment on skeletal health are largely unknown. Since estrogen deficiency is associated with various detrimental skeletal effects, we evaluated in this cross‐sectional posttreatment study vertebral body morphology, dimensions and endplates, and intervertebral disks by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole or placebo. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during prepuberty or early puberty; males with constitutional delay of puberty received letrozole or placebo in combination with low‐dose testosterone for 1 year during early or midpuberty. In males with idiopathic short stature, mild vertebral body deformities were found in 5 of 11 (45%) letrozole‐treated subjects, whereas in the placebo group no deformities were detected (p = .01). In the cohort of males with constitutional delay of puberty, a high prevalence of endplate and intervertebral disk abnormalities was observed in both the letrozole‐ and the placebo‐treated groups. We conclude that AI therapy during prepuberty or early puberty may predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. If AIs are used in growth indications, follow‐up of vertebral morphology is indicated.

Zoledronic acid treatment in children with osteogenesis imperfecta.

Background: Intravenous disodium pamidronate has become an established treatment in osteogenesis imperfecta (OI). Another bisphosphonate, zoledronic acid, has been indicated for the treatment of adult osteoporosis. We studied its efficacy and safety in children with mild OI. Methods: Patients were treated for 1.0–3.2 years with 0.05 mg/kg zoledronic acid intravenously every 6 months as part of their clinical care. They were carefully followed for clinical and biochemical parameters, side effects, bone mineral densities (BMD) and compression fractures. Results: The study included 17 patients (age 1.5–16.8 years) with type I OI. They had sustained altogether 73 fractures; 9 had compression fractures. During the treatment, 6 patients suffered in total 10 new long-bone fractures. The median lumbar spine areal BMD z-score increased from –2.0 to –0.7 during 2 years of treatment. The infusions were associated with a transient decrease in serum calcium and phosphate and a significant increase in serum PTH. Two patients developed symptomatic hypocalcemia. Bone turnover markers decreased during the treatment. Conclusions: Intravenous zoledronic acid is an effective mode of treatment in children with OI. The treatment response is comparable to pamidronate but the infusion protocol is more convenient. Further studies are needed to establish optimal dosing and long-term safety.

Impact of aromatase inhibitor therapy on bone turnover, cortical bone growth and vertebral morphology in pre- and peripubertal boys with idiopathic short stature.

In this randomized placebo-controlled study we examined the influence of aromatase inhibition on bone turnover, cortical bone growth, and vertebral body morphology in peripubertal boys. Thirty peripubertal boys with idiopathic short stature were treated with the aromatase inhibitor letrozole or placebo for 2 years. During treatment and posttreatment follow-up, dual-energy X-ray absorptiometry (DXA)-assessed bone mineral density, metacarpal index (MCI), and markers of bone turnover were examined. Vertebral morphology was examined by DXA after cessation of treatment. In letrozole-treated boys, the concentrations of the bone resorption marker urine aminoterminal telopeptide of type I collagen initially increased and thereafter slowly declined while the concentrations of the bone formation markers serum aminoterminal propeptide of type I collagen and serum alkaline phosphatase remained unchanged or slightly increased, respectively. In placebo-treated boys, all markers of bone turnover increased significantly during treatment. Among those who progressed into puberty, metacarpal index (MCI) increased more in the letrozole-treated than in the placebo-treated boys during treatment (25 vs. 9%, p = 0.007). The change in MCI correlated with the testosterone-to-estradiol ratio (r = 0.59, p = 0.02). Vertebral deformities were detected in 6 out of 13 boys receiving letrozole and in 4 out of 11 receiving placebo (p = 0.70). Aromatase inhibition suppresses bone turnover, possibly through an androgen-mediated effect. In pubertal boys, treatment stimulates cortical bone growth by increasing the testosterone-to-estradiol ratio.

Impaired bone health and asymptomatic vertebral compressions in fracture‐prone children: A case‐control study

Frequent fractures in children may be a sign of impaired bone health, but it remains unestablished when and how fracture‐prone children should be assessed. This prospective study elucidated skeletal characteristics and predisposing factors in children with recurrent fractures. Findings were used to establish guidelines for screening. During a 12‐month period we recorded fracture history for all children (n = 1412) treated for an acute fracture at a large university hospital. All apparently healthy children over 4 years of age, who had sustained: (1) at least one vertebral fracture; (2) two long‐bone fractures before age 10 years; or (3) three long‐bone fractures before age 16 years, were recruited. They underwent dual‐energy X‐ray absorptiometry (DXA), laboratory tests, and spinal radiography. Information regarding family history and lifestyle factors were collected. Findings were compared with healthy controls. Sixty‐six fracture‐prone children (44 males, mean age 10.7 years; 5% of all children with fractures) were identified. Altogether, they had sustained 183 long‐bone fractures (median 3, range 0–7); 11 children had sustained vertebral fracture(s). Patients had significantly lower bone mineral density (BMD) at lumbar spine (p < 0.001), hip (p = 0.007), and whole body (p < 0.001) than the controls; only 5 children (8%) had a BMD Z‐score < −2.0. Asymptomatic vertebral compressions were prevalent, especially in those under 10 years of age. Hypercalciuria (11%) and hyperphosphaturia (22%) were significantly more prevalent than in controls. Serum concentration of 25‐hydroxyvitamin D (S‐25OHD) was below 50 nmol/L in 55%; low levels were associated with low BMD and vertebral compressions. The fracture‐prone children had lower calcium intake, less physical activity, and more often had siblings with fractures than the controls. The findings suggest that a thorough pediatric evaluation, including DXA and spinal radiography, is often indicated already after a second significant low‐energy fracture in children, in order to detect potentially preventable adverse lifestyle factors and nutritional deficits and to identify those with compromised overall bone health.

Long-term skeletal consequences of childhood acute lymphoblastic leukemia in adult males: a cohort study.

OBJECTIVE Long-term health sequelae of childhood-onset acute lymphoblastic leukemia (ALL) remain largely unknown. Low bone mineral content (BMC) and bone mineral density (BMD) are recognized complications, but it is unknown whether these persist until adulthood. We evaluated skeletal characteristics and their association with ALL therapy in long-term male ALL survivors. DESIGN This cross-sectional cohort study included 49 long-term male ALL survivors and 55 age-matched healthy males. METHODS BMD and compression fractures were assessed by dual-energy X-ray absorptiometry; blood biochemistry was obtained for parameters of calcium homeostasis. RESULTS The ALL survivors (median age 29 years, range 25-38 years), assessed 10-38 years after ALL diagnosis, had lower lumbar spine (P<0.001), femoral neck (P<0.001), and whole-body (P=0.017) BMD than expected based on normative values. When compared with the controls (median age 30 years, range 24-36 years), the ALL survivors had lower lumbar spine BMC (P=0.014), lower whole-body BMC (P<0.001), and lower whole-body BMD (P<0.001), but the differences were partly explained by differences in height. Altogether, 20% of the ALL survivors had spinal compression fractures, but these were equally prevalent in the controls. Males diagnosed with ALL before age 5 years had significantly lower BMD values. Other recognized risk factors included untreated hypogonadism, vitamin D deficiency, hypophosphatemia, low IGF-binding protein-3, and low physical activity. CONCLUSIONS At young adulthood, long-term male ALL survivors have significantly reduced BMC and BMD and a high prevalence of spinal compression fractures. Careful follow-up and active treatment of the recognized risk factors are warranted.

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

A Novel Splice Mutation in PLS3 Causes X-linked Early Onset Low-Turnover Osteoporosis

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X‐chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X‐linked inheritance. Phenotyping was performed on 19 family members and whole‐exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73‐24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N‐terminal calcium‐binding EF‐hand domain and abolishes all calcium‐ and actin‐binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment.

Shwachman–Diamond syndrome is associated with structural brain alterations on MRI

Shwachman–Diamond syndrome (SDS) is an autosomal recessive condition that results from mutations in the SBDS gene, at chromosome 7q11. Main features include exocrine pancreatic failure, neutropenia and skeletal dysplasia. This study investigated brain structures by magnetic resonance imaging (MRI) in patients with SDS. MRI of the brain was performed in nine patients (7 males, age range 7–37 years) with SDS and mutations in the SBDS gene and in 18 age‐ and gender‐matched controls. MRI images were assessed visually, and volumetric analyses of the brain matter and structural midsagittal measurements were performed. Eight out of nine SBDS mutation‐verified patients reported learning difficulties. Patients with SDS had smaller occipitofrontal head circumferences than the controls (Z‐score −1.3 vs. +0.3, P = 0.021), and decreased global brain volume (1.74 L vs. 1.94 L, P = 0.019); both gray matter (P = 0.042) and white matter (P = 0.007) volumes were reduced. Patients with SDS had no macroscopic brain malformations, but they had significantly smaller age‐ and head size‐adjusted areas of posterior fossa (P = 0.006), vermis (P = 0.002), corpus callosum (P = 0.020), and pons (P = 0.002), and significantly larger cerebrum‐vermis ratio (P < 0.0001) than the healthy controls. SDS patients had structurally smaller posterior fossa and cerebellar vermis, corpus callosum, and brainstem than the healthy controls. The MRI findings may be related to the neuropsychological features described in SDS.