New gene discoveries in skeletal diseases with short stature

In the last decade, the widespread use of massively parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal dysplasias, spondyloepimetaphyseal dysplasias, and some monogenic forms of isolated short stature. Some examples of novel genetic mechanisms leading to skeletal conditions with short stature will be described. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. In summary, we review the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, for an optimal management of the disease, and for therapeutic innovations.Peer reviewe

Candida prevalence in saliva before and after oral cancer treatment

Background: Previous studies have shown an increased prevalence of candidiasis in patients receiving radiotherapy for head and neck cancer. However, little is known of the effect the different cancer treatment modalities have on the oral Candida status. Objective and hypothesis: The objective of this study was to investigate the change in salivary Candida status of oral squamous cell carcinoma (OSCC) patients undergoing cancer treatment. The hypothesis was that cancer treatments change the oral microbial environment favouring an increase in the prevalence of more pathogenic non-albicans Candida (NAC). Methods: We collected paraffin-stimulated saliva from 44 OSCC patients before surgery and after a minimum of 19 months of follow-up. Chromagar, Bichro-Dupli-test and API ID 32 C were used for identification of different Candida species and results were analysed statistically. Results: At both timepoints, 75% of samples were Candida positive with C. albicans being the most common yeast. NAC strains were present in 16% of the pre-operative samples and 14% of the follow-up samples. The NAC species found were C. dubliniensis, C. krusei, C. guilliermondii (preoperatively only) and C. glabrata (at follow-up only). In 73% of the cases, the salivary Candida status remained unchanged. There was an 18% increase in the prevalence of candidiasis. However, the different treatment modalities did not statistically significantly affect the Candida status of the patients. Conclusion: The intraindividual prevalence of salivary Candida among OSCC patients seems to be stable and different treatment modalities have little to no effect on the salivary Candida status. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).Peer reviewe

Pretreatment tumor sampling and prognostic factors in patients with soft-tissue sarcoma of the head and neck

Correction: DOI10.1007/s00405-021-07205-6 Early AccessDEC 2021Background Insufficient preoperative work-up and consequent intralesional or marginal resection of soft-tissue sarcomas of the head and neck (STSHNs) is common. Methods This retrospective cohort study comprised 63 patients with STSHN treated at the Helsinki University Hospital between 2005 and 2017. We assessed the effect of pretreatment tumor sampling on surgical margin status and need for supplemental surgery, as well as prognostic factors and survival. Results The lack of representative pretreatment biopsy specimen was associated with unfavorable margin status. Primary surgery at a non-academic center was associated with need for supplemental surgery. The 3-year overall survival (OS) was 68%, disease-specific survival (DSS) 71%, and recurrence-free survival (RFS) 61%. Higher tumor grade and primary tumor size over 5 cm were associated with reduced DSS. Conclusions Diagnosis and management of STSHNs should be centralized to experienced academic centers. Decision-making between needle biopsy, open biopsy, or upfront radical surgery depends on tumor location and size.Peer reviewe

Dental health in patients with and without HPV-positive oropharyngeal and tongue cancer

BackgroundHuman papilloma virus is associated with oral and oropharyngeal cancer. Our aim was to examine oral health in patients with oropharyngeal (OPSCC) and oral tongue cancer (OTSCC), expecting better oral health among OPSCC patients.Material and methodsFifty-five OPSCC patients with known HPV status and 59 OTSCC patients were randomly selected from a list of consecutive patients of the Helsinki University Hospital, Finland. Oral health was assessed from panoramic jaw radiographs. Total Dental Index (TDI) summarizing the dental health status was calculated and Finnish population study data were used for comparison. Descriptive statistics were used for analyses.ResultsPatients with HPV-positive OPSCC had higher periapical lesion index compared with HPV-negative OPSCC patients or with OTSCC patients. Residual roots were more common among OPSCC patients compared with OTSCC patients, because of their higher occurrence among HPV-negative OPSCC patients compared with OTSCC patients. Similarly, modified TDI score was significantly higher among OPSCC patients than among OTSCC patients, because of higher TDI score among HPV-negative OPSCC patients compared with OTSCC patients. OPSCC patients more often used a removable prosthesis than OTSCC patients. Dental health of the cancer patients was poorer when compared with the population data.ConclusionsOur study hypothesis was only partly confirmed. Periapical lesions were more prevalent among HPV-positive OPSCC patients, compared with the other groups. The number of residual roots was higher among HPV-negative subgroup. Thus, OPSCC patients had worse oral health parameters than OTSCC patients.Peer reviewe

PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants

The Summary Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis. Introduction The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features. Methods Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3. Results In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects. Conclusion Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.Peer reviewe

Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study

CONTEXT\nObservations in rodents suggest that osteocalcin (OC) participates in glucose metabolism. Based on human studies, it remains unclear whether circulating OC is simply a bone turnover marker (BTM) or also a mediator in interactions between the skeleton and glucose homeostasis.\nOBJECTIVE\nThe objective of the study was to determine the responses of BTMs, including OC, to oral glucose tolerance test (OGTT) in a case-control setting.\nDESIGN AND PATIENTS\nThirty-four normoglycemic young adults [mean age 19 y (SD 2.3)] with severe childhood-onset obesity and their gender- and age-matched nonobese controls underwent a standard 2-hour OGTT.\nMAIN OUTCOME MEASURES\nGlucose, insulin, and six BTMs including total and carboxylated OC (cOC) were determined at baseline and at 30, 60, 90, and 120 minutes during OGTT.\nRESULTS\nThe obese and control subjects were similar in height; the mean body mass indices were 40.4 and 21.9 kg/m(2), respectively. The homeostasis model assessment index was 2.7 times greater in the obese subjects. All BTMs, except bone-specific alkaline phophatase, were lower in the obese subjects compared with the controls: the differences at baseline were 40%, 35%, 17%, 31%, and 32% for N-terminal propeptides of type I collagen, cross-linked telopeptides of type I collagen, tartrate-resistant acid phosphatase, total OC, and carboxylated OC (P &lt; .05 for all) after adjusting for whole-body bone area. All BTMs decreased during OGTT. The relative values for the OGTT responses for total, but not for cOC (measured as area under the curve) differed between the two groups (P = .029 and P = .139, respectively): the decrease in total OC during the OGTT was less pronounced in the obese subjects. Responses in other BTMs were similar between the groups. No associations were observed between glucose metabolism and OCs during OGTT with linear regression.\nCONCLUSIONS\nBone turnover markers were substantially lower in obese subjects compared with controls. Total OC and cOC showed less pronounced decrease during the OGTT in obese subjects compared with controls, whereas other BTMs responded similarly in the two groups. The role of OC, if anything, in glucose homeostasis is indirect and may be mediated via other factors than glucose or insulin.</p

Iron status in early childhood is modified by diet, sex and growth : Secondary analysis of a randomized controlled vitamin D trial

Background & aims: During early childhood the risk of iron deficiency (ID) is high. Serum ferritin serves as a marker of iron status. We explored prevalence of ID and iron deficiency anemia (IDA), and identified determinants of iron status in infants and toddlers. Methods: We performed a secondary analysis of the Vitamin D intervention in infants (VIDI) study in Finnish healthy term infants. According to study protocol, at 12- and 24-months of age iron status, growth and dietary intakes were evaluated. ID was defined as serum ferritin Results: ID prevalence increased from 14% in infants to 20% in toddlers. IDA prevalence was 3% at both time points. In infants, ID and IDA were more common in boys than in girls (19% vs. 9%, p = 0.001 and 5% vs. 1%, p = 0.039) but no sex-difference in toddlers was observed. Of infants, 30% had daily iron intake below average requirement of 5 mg/day. Higher daily iron intake per body weight (mg/kg) independently associated with higher infant serum ferritin (B (95% CI) 0.30 (0.04, 0.56), p = 0.026). Correlation between iron intake and ferritin was stronger in infants with ID than in infants without ID. Breastfeeding was more common (63% vs. 35%, p < 0.001) among ID infants than in infants without ID. In toddlers, frequent consumption of milk products independently associated with lower ferritin (B (95% CI) -0.03 (-0.05, -0.01), p = 0.001). Consumption of meat and fish associated with better iron status. Serum ferritin at both time points associated with duration of gestation and growth. The association of growth and ferritin was age-dependent in boys, while in girls, faster growth associated consistently with lower ferritin. Conclusions: In Northern European healthy infants and toddlers ID is common. The intake of iron remains below recommendations and food consumption and iron intake associate with iron status. Further studies are warranted to assess significance of ID on child development and clinical health outcomes. (C) 2021 The Authors. Published by Elsevier Ltd.Peer reviewe