Diana-Alexandra Ertl

Background/aim: Hyperparathyroidism (HPTH) is a common feature in patients with X-linked hypophosphatemia (XLH), especially when treated with vitamin D analogues and phosphate supplements. Although the exact mechanism is not clear, it is assumed that prolonged intake of phosphate supplements stimulates parathyroid hormone (PTH) secretion. We prospectively assessed the effect of burosumab on PTH levels in children with XLH. Patients and methods: 37 children (8.8 ± 3.2 years) were switched from phosphate supplements and vitamin D analogues to burosumab and completed at least three years of therapy. Biochemical parameters of calcium-phosphate homeostasis were measured at baseline and prospectively every 6 months. Target serum phosphate under burosumab was >1.2 mmol/L (>3.7 mg/dL). Results: After three years of treatment there was a global increase of PTH levels from 39.1 ± 18.2 to 54.8 ± 27.6 ng/L (p = 0.001) (normal range 18.5-88 ng/L). Four of 37 subjects (10.8%) developed secondary HPTH after 3 years. None developed tertiary hyperparathyroidism. Subjects who developed HPTH had higher serum phosphate at M36 (1.33 vs 1.19 mmol/L, p = 0.11, respectively), in comparison to those without HPTH. A significant increase in PTH was correlated with the increase in serum phosphate >1.3 mmol/L (p = 0.012); serum phosphate positively and independently correlated with PTH in logistic regression analysis (OR = 2.1, CI95%=1.1-3.8, p = 0.021). Conclusion: We suggest that higher serum phosphate levels in the context of prolonged treatment with burosumab may stimulate PTH secretion in some patients with XLH, leading to HPTH. Careful follow-up and preventive measures to limit the development of secondary HPTH should be applied in treated children.

Objective: Autosomal dominant hypocalcemia type 1 (ADH1) results from activating CASR variants, causing parathyroid hormone (PTH) suppression and abnormal renal calcium handling. Management is challenging, as hypoparathyroidism is associated with inappropriate renal calcium wasting, leading to hypercalciuria, nephrocalcinosis, and renal impairment. We evaluated long-term outcomes of continuous subcutaneous PTH(1–34) infusion (CSPI) in children with ADH1 refractory to standard of care therapy (SOC). Design: Single-center observational study. Methods: Five children with genetically confirmed ADH1 were treated with CSPI between 2012 and 2017 and followed for up to 11 years. Clinical outcomes, biochemical parameters, and renal findings were assessed under SOC and CSPI. Serum calcium, phosphate (standard deviation score, SDS), magnesium, alkaline phosphatase, eGFR, urinary calcium/creatinine ratio (relative to the age-specific 95th percentile), and fractional calcium excretion (FECa) were analyzed using linear mixed-effects models. Results: Hypocalcemic seizures and emergency visits decreased, growth was appropriate, and no treatment-related adverse events occurred over a median 7-year follow-up. CSPI was associated with higher serum calcium (P < .001) and lower serum phosphate (P < .001). Urinary calcium/creatinine ratios, expressed relative to the age-specific 95th percentile, were lower under CSPI (P < .001). FECa was approximately 8% lower under CSPI (P = .014), suggesting improved renal calcium handling. Renal function remained stable despite progression of nephrocalcinosis in 4/5 patients. Conclusion: SPI appears to be a safe and effective long-term treatment in pediatric ADH1, improving mineral homeostasis and renal calcium handling. Prospective multicenter studies are needed to assess long-term skeletal outcomes and optimize dosing strategies.

Background: X-linked hypophosphatemia (XLH) is a rare disease caused by PHEX variants. Besides rickets, XLH leads to disproportionately short stature, which develops during the first months of life. Burosumab afforded minimal improvement of growth in children above the age of 4 years. No data are available on growth, including body mass index, of XLH children who started burosumab at a very young age, i.e., between 1 and 4 years. Methods: We performed a prospective follow-up of growth and other XLH-related outcomes in XLH children who started burosumab before the age of 4 years. We compared these children 1:2 with a historical cohort of XLH children who started vitamin D analogs and phosphate supplements before the age of 4 years. Results: We included 15 children treated with burosumab and 31 children treated with vitamin D analogs and phosphate supplements. In the burosumab-treated group, mean ± SD for age at therapy baseline was 2.1 ± 0.7 years (range: 1–2.9 years). They were treated with oral phosphate and active vitamin D for 1.7 ± 0.8 years before switching to burosumab. From birth to burosumab start, they presented a decline in height standard deviation score (SDS) from −0.3 ± 0.7 to −1.4 ± 0.8 (mean ± SD), respectively, P < 0.001. On burosumab, height SDS did not decline further during the first 2 years of treatment: mean ± SD 0.1 ± 0.6 (range: −0.7–1.3 SDS) after 1 year (P = 0.16) and 0.0 ± 0.7 SD (range: −0.6–1.4 SDS) after 2 years (P = 0.54). Burosumab did not correct the acquired height deficit, as children had a difference in height SDS of −1.5 SDS after 2 years of therapy when compared to birth length SDS (P = 0.04). BMI SDS did not significantly change during the first 2 years on burosumab. Children treated with vitamin D analogs and phosphate supplements started treatment at a mean ± SD age of 1.3 ± 0.7 years (range: 0.1–3.0 years) and presented a continuous decline in height SDS of 0.7 ± 0.9 SDS (range: −2.6–1) during the first 2 years of therapy (P < 0.001) and up to 4 years of age (−1.8 ± 0.9 SDS to −1.9 ± 0.9, respectively). BMI SDS increased by 0.5 ± 0.9 SDS (range: −0.6–1.9) during the same period (P = 0.006). Conclusion: We present data from the largest pediatric XLH cohort of very young children treated with burosumab over a follow-up period of 2 years. Our data suggest that, in contrast to the combination of vitamin D analogs and phosphate supplements, burosumab prevents further height deficit in XLH children, even at a period of life associated with high growth velocity. In addition, burosumab prevents the early and excessive weight gain associated with the development of XLH in children. Significance statement: Most patients with X-linked hypophosphatemic rickets (XLH) present with short stature. This is the first large study on XLH children younger than 5 years treated with burosumab since a mean age of 2.1 years. We analyzed growth over a period of 2 years of therapy. Our data show that, in XLH toddlers, burosumab therapy prevents the further loss of height and the weight gain observed in patients treated with oral phosphate and active vitamin D therapy at the same age. As burosumab leads to better long-term outcomes in these children, we hope that our work will encourage the early use of burosumab and motivate further research in this field.

X-linked hypophosphatemia (XLH) is a phosphate-wasting disorder caused by increased fibroblast growth factor 23 (FGF23); it leads to skeletal deformities, muscle weakness, and pain. In a pediatric phase 3 trial, the FGF23 inhibitor burosumab improved rickets severity and bone biochemistry. The current study characterizes health-related quality of life (HRQL) in children with XLH using real-world data collected at centers in France for the International XLH Registry from April 2017 to January 2024. Age-appropriate versions of the Pediatric Quality of Life Inventory were completed. Data from the first completion after registry entry were analyzed. Variation in scores by demographic, medical history, and treatment history variables was assessed using bivariate analysis. The data were collected from 96 children (59% female; mean age 8.1 [SD 4.4] yr); 82% were taking burosumab. Mean total, summary, and domain scores were similar in different age groups. Mean total score (74.2 [SD 14.1]), Psychosocial Health Summary (72.0 [16.8]), and Physical Health Summary (78.3 [12.3]) scores were lowest in patients aged 5-7 yr and highest in patients aged 13-17 yr (81.0 [13.3], 79.8 [14.1], and 83.1 [15.2]). The mean Psychosocial Health Summary score was lower than the Physical Health Summary score for all patients combined (77.8 [13.9] vs 81.7 [14.3]). Better total scores were associated with not currently taking phosphate/vitamin D analogs, better Psychosocial Health Summary scores with higher serum phosphate and not taking phosphate/vitamin D analogs, and better Physical Health Summary scores with lower serum PTH and currently taking burosumab. Patients with XLH who were taking burosumab at the time of PedsQL completion had better total and summary scores than children with other chronic musculoskeletal disorders. Children aged 5-7 yr had worse HRQL than a healthy Dutch sample. Overall, better HRQL was associated with higher serum phosphate levels and burosumab treatment.

Objectives: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking. Design: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements. Materials and methods: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs. Results: A total of 398 patients were included. Mean FHs were the following: for group 1, −2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7 cm in men and 148.6 ± 6.5 cm in women; for group 2, −1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5 cm in men and 153.1 ± 7.2 cm in women; and for group 3, −1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5 cm in men and 154.7 ± 6 cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (−2.08 ± 1.18) was lower than in female (−1.70 ± 1.12) (P = .002). Conclusion: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement.

Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height. Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls. We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models. Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy. Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.

Introduction Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations). Methods We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5. Results We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median – 2.2 SDS vs. – 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median – 2.8 SDS vs. – 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1–2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6–5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5–3.1 for rhGH-treated iPPSD5 (n = 2). Conclusion Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.

Background: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies. Results: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)₂D increased dramatically under burosumab therapy. Conclusion: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations in the biomineralization-associated alkaline phosphatase gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms include skeletal hypomineralization and extra-skeletal manifestations such as pyridoxine (B6)-responsive seizures due to impaired cerebral B6 passage. Since the introduction of enzyme replacement therapy (ERT), skeletal manifestations and B6-responsive seizures were reported to improve significantly. Nevertheless, there is an increasing evidence of B6-independent neurological manifestation of HPP including HPP-associated encephalopathy. Here, we present for the first time the brain alterations of an infant with neonatal HPP who died of neurological complications at the age of 5 months despite early initiation of ERT. CSF analysis showed normal concentrations of biogenic amines reflecting sufficient intracellular B6 availability. Postmortem histopathology revealed severe, localized affection of the cerebral cortex including cortical lesions in layers 2 and 3 in direct proximity to TNSALP-expressing neurons and hippocampal sclerosis. Our findings confirm that TNSALP deficiency may lead to a severe encephalopathy. We hypothesize that HPP-associated encephalopathy resistant to currently available ERT may develop in addition and probably independently of typical B6-responsive seizures in some patients. Prospective, controlled studies with close neurological follow-up including brain imaging are needed to identify patients at risk for severe neurological symptoms despite ERT.

Zusammenfassung: Fast 80 Jahre nach der erstmaligen Beschreibung ist die Diagnose des Pseudohypoparathyreoidismus für viele Ärzte immer noch eine Herausforderung. Die Vielfalt der klinischen Merkmale und des Verlaufs macht die Diagnosestellung kompliziert. Einige der Patient_innen bleiben unerkannt oder werden erst im Erwachsenenalter diagnostiziert. Nachdem der pathophysiologische Mechanismus verstanden wurde, wurde klar, dass auch andere, verwandte Störungen in Betracht gezogen werden sollten, wenn eine Nebenschilddrüsenhormonresistenz oder ein spezifischer Skelettphänotyp auftritt. Rezente Studien haben gezeigt, dass Mutationen in anderen Genen als dem schon bekannten GNAS zu Störungen der PTH/PTHrP-Signalübertragung führen, was einige der gemeinsamen Merkmale des klassischen Pseudohypoparathyreoidismus erklärt. In diesem Artikel fassen wir die aktuellen Literaturdaten zur neuen Nomenklatur der Störungen des PTH/PTHrP-Signalling, deren Diagnostik und Therapie zusammen, und wir unterstreichen die Notwendigkeit eines multidisziplinären Managements der Patienten. Obwohl diese Krankheiten selten sind, weisen sie möglicherweise schwerwiegende und langanhaltende Komplikationen auf. Daher ist es wichtig, dass auch Patient_innen mit milden Symptomen oder diskretem Phänotyp erkannt, diagnostiziert, behandelt und adäquat langzeitbetreut werden.