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Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

PurposeAchondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.MethodsAfter completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.ResultsIn children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Abstract Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions.

Abstract Background: Achondroplasia is a disorder caused by specific mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) protein. Open-label, phase 2 trials in children with achondroplasia showed that administration of vosoritide, an analogue of C-natriuretic peptide, resulted in sustained increases in annualized growth velocity. Methods: This international, randomized, double-blind, phase 3 trial compared once-daily subcutaneous administration of vosoritide, at a dose of 15 μg per kg of body weight, with placebo in children with achondroplasia aged 5 to

Context Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated. Objective This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH. Methods Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PPi)—a potent inhibitor of tissue calcification—were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification. Results We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PPi, 14 patients (45%) showed decreased plasma PPi concentrations; however, PPi concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification. Conclusion Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PPi on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size. [ABSTRACT FROM AUTHOR]

The SUNFLOWER study was initiated in Japan and South Korea to clarify the course of X-linked hypophosphatemic rickets/osteomalacia (XLH); delineate its physical, mental, and financial burdens; and collect information on treatment. Here, we report cross-sectional data at the time of patient enrollment to better understand the real-world management and complications in patients with XLH and examine the effect of XLH on quality of life (QOL). This is an ongoing, longitudinal, observational cohort study of patients with a diagnosis of XLH. Data from 147 patients (118 in Japan and 29 in South Korea) were evaluated. In total, 77 children (mean age, 9.7 yr; 67.5% female) and 70 adults (mean age, 37.6 yr; 65.7% female) were enrolled. PHEX gene mutations were confirmed in 46/77 (59.7%) children and 37/70 (52.9%) adults. Most patients in both age groups were receiving a combination of phosphate and active vitamin D at baseline. The mean height Z-score was −2.21 among adults (male: −2.34; female: −2.14). The mean Rickets Severity Score in children was 1.62. Whereas children appeared to have low pain levels (mean revised faces pain scale score, 1.3), adults reported mild-to-moderate pain (mean Brief Pain Inventory pain severity, 2.02). Mean QOL in children (assessed using the 10-item short-form health survey for children) was low, with a score below normative level for physical functioning. In adults, results from the Western Ontario and McMaster Universities osteoarthritis index indicated the presence of pain, stiffness, and decreased physical function. The respective mean total days/year of work/school non-attendance due to symptoms/complications and management of XLH were 0.7 and 3.0 among adults, and 6.4 and 6.1 among children. Our findings reconfirmed a relationship between disease and QOL in patients with XLH. We anticipate that these data will be important in enabling clinicians to understand the daily reality of patients with XLH. Lay Summary: X-linked hypophosphatemic rickets/osteomalacia (XLH) is a rare, PHEX gene mutation-linked disorder that causes weak bones and bone deformities. The ongoing SUNFLOWER study aims to collect information on Japanese and South Korean patients with XLH to better understand how this disease progresses over time, its impact on quality of life (QOL), and how it is currently being treated. Data from 147 patients (77 children and 70 adults) were evaluated. Over half of the adults and children included in this study had a confirmed PHEX gene mutation. Although most patients were receiving conventional therapy for XLH, laboratory tests revealed that they had underlying issues with bone health and that their growth rates were still being negatively affected. Bone-related complications were more common among adults than children. Children reported low levels of pain, whereas adults reported mild-to-moderate pain. Children with XLH scored low for physical functioning on QOL tests. Adults with XLH reported pain, stiffness, and decreased physical function on QOL tests. XLH had a larger impact on children's school attendance than adults' work attendance. Our findings will help improve understanding of the daily reality of XLH patients in Japan and South Korea. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue‐nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease‐causing variants; 4.4% had variants of uncertain significance. Disease‐causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%–23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty‐three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population. [ABSTRACT FROM AUTHOR]

Monozygotic (MZ) twins originate from a single fertilized egg, making them genetically identical at the time of conception. However, postzygotic somatic mutations (PZMs) can introduce genetic differences after separation. Although whole-genome sequencing (WGS) sheds light on somatic mutations in cancer genomics, its application in genomic studies of MZ twins remains limited. In this study, we investigate PZMs in 30 healthy MZ twin pairs from the Osaka University Center for Twin Research using WGS (average depth = 23.8) and a robust germline-calling algorithm. We find high genotype concordance rates (exceeding 99%) in MZ twins. We observe an enrichment of PZMs with variant allele frequency around 0.5 in twins with highly concordant genotypes. These PZMs accumulate more frequently in non-coding regions compared with protein-coding regions, which could potentially influence gene expression. No significant association is observed between the number of PZMs and age or sex. Direct sequencing confirms a missense mutation in the ANKRD35 gene among the PZMs. By applying a genome-wide mutational signature pattern technique, we detect an age-related clock-like signature in these early postzygotic somatic mutations in MZ twins. Our study provides insights that contribute to a deeper understanding of genetic variation in MZ twins. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium and elevated serum phosphorus levels. Patients who do not recover parathyroid function after surgeries or have nonsurgical causes involving congenital and metabolic diseases, require long-term use of active vitamin D and calcium supplementation as conventional therapy in Japan. This study aimed to estimate prevalence of chronic hypoparathyroidism and investigate its disease etiology, patient characteristics, and treatment in Japan, using a health insurance claim database. Individuals who were available in the 4-yr observation period spanning 2015–2018 (2015–2017 for look-back and 2018 for prevalence estimation) were eligible for the denominator. Chronic hypoparathyroidism was defined as individuals who had both a record of prescription of conventional therapy for hypoparathyroidism in 2018 and a record of relevant surgery, radiotherapy, or disease at least 6 mo apart. Among the denominator (N = 2 241 717), 509 patients with chronic hypoparathyroidism were identified (mean age of 49 yr). The standardized prevalence of chronic hypoparathyroidism in 2018 was 38.3 (95% CI: 33.4–43.6) per 100 000 individuals, with 37.0 (32.2–42.3) and 1.2 (0.8–2.0) per 100 000 for postoperative and nonoperative causes, respectively. Six percent of the patients had chronic kidney disease as a comorbidity. Chronic hypoparathyroidism had heterogenous causes, with thyroid malignancy and 22q11.2 deletion syndrome being the most common postoperative and nonoperative causes, respectively. The mean duration of prescribed vitamin D and calcium was 963 and 629 d, respectively, during the 4-yr period. The prevalence of chronic hypoparathyroidism was similar but slightly higher than estimates reported for the United States and Europe, which may be due to the differences in study designs and high healthcare accessibility in Japan. Our study suggests that there is a nonnegligible number of patients, ~48 500 patients, with chronic hypoparathyroidism in Japan. Graphical Abstract Lay Summary: Patients with chronic hypoparathyroidism who produce abnormally low levels of parathyroid hormone require long-term treatment for signs and symptoms (eg, tetany, tingling, or burning in the fingertips) caused by low serum calcium and high serum phosphorus levels. Although these patients have clinical and economic burdens due to their disease status, including higher risk of comorbidities (eg, chronic kidney disease), epidemiological data on chronic hypoparathyroidism are scarce in Asian countries. Thus, the insurance claims database was used to investigate the prevalence of chronic hypoparathyroidism in Japan. Patient characteristics and treatment patterns were also assessed. We estimated that the prevalence was 38.3 (95% CI: 33.4–43.6) per 100 000 individuals in 2018, with 37.0 (32.2–42.3) and 1.2 (0.8–2.0) per 100 000 for postoperative and nonoperative causes, respectively. These findings suggest that there is a nonnegligible number of patients with chronic hypoparathyroidism, as the prevalence corresponds to ~48 500 patients nationwide. The patients with hypoparathyroidism are expected to increase in the coming years with an upward trend of primary disease, especially increasing diagnostic and technological advances for thyroid malignancies and congenital disorders. Our real-world data could be useful for improving the understanding of disease epidemiology of chronic hypoparathyroidism in Japan. [ABSTRACT FROM AUTHOR]

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records‐based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH‐treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non‐GH‐treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH‐treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non‐GH‐treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions. [ABSTRACT FROM AUTHOR]