Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.

The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.

Skeletal outcome in long-term survivors of childhood high-risk neuroblastoma treated with high-dose therapy and autologous stem cell rescue.

High-dose therapy and hematopoietic stem cell transplantation (HSCT) have been shown to improve survival rates in high-risk neuroblastoma (HR-NBL), but may cause adverse effects on the growing skeleton. We studied skeletal health in a national cohort of long-term survivors of HR-NBL (n=21; age 16-30 years, median 22 years) and in 20 healthy age- and sex-matched controls. In addition to clinical evaluation and measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry, we performed spinal magnetic resonance imaging. Skeletal complications were categorized according to Common Terminology Criteria for Adverse Events (CTCAE). Altogether, 18/21 survivors presented with at least one skeletal adverse event according to CTCAE, the most common skeletal complications being short stature (n=14) and osteopenia (n=13). Altogether, 38% of the subjects had a severe complication (CTCAE score ⩾3) including bilateral slipped capital femoral epiphyseolysis in 3/21. Fracture rate was not increased. In spinal MRI, no vertebral fractures were found and degenerative intervertebral disc changes were equally prevalent in survivors and controls. BMD was lower in survivors than controls, but differences became non-significant when adjusted for bone size. In conclusion, skeletal late complications are common and can significantly impair the quality of life in young adult survivors of HR-NBL treated with high-dose protocols and HSCT.

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.

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.

Fetal urinoma: two new cases and a review of the literature.

OBJECTIVE: To evaluate the functional prognosis of kidneys affected prenatally by urinomas. METHODS: This was a retrospective review of cases of fetal urinoma reported in the literature, as well as two of our own cases. RESULTS: Twenty-three patients with a prenatal diagnosis of urinoma (five bilateral) were included in the analysis. Postnatal ipsilateral renal function was observed in only six of the 28 renal units (i.e. around 20%). CONCLUSIONS: Although the precise causes of urinomas are still unknown, this review shows that in the event of a fetal urinoma, the probability of a non-functional dysplastic ipsilateral kidney lies at around 80%. In-utero puncture only appears to be justified in cases where fluid accumulation has mass effects on adjacent major structures.