The parathyroid hormone receptor 1 (PTH1R) transmits stimuli provided by parathyroid hormone (PTH) and PTH-related protein (PTHrP) and thus plays key roles in calcium and phosphate homeostasis as well as skeletal development. Variants in PTH1R have been linked to several conditions including Jansen's metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, Primary Failure of Tooth Eruption and Eiken syndrome. Here, we report a novel skeletal phenotype identified in two unrelated families associated with PTH1R variants. The clinical features include brachydactyly type E (BDE), mild short stature, and dental anomalies. A novel heterozygous PTH1R substitution (p.E469K) was identified in affected members of Family 1, while the affected individual from Family 2 had a previously described heterozygous de novo substitution (p.E465K); these two mutated sites lie within helix 8 of the PTH1R. Cell-based assays revealed reduced cell surface expression, as well as impaired basal and PTH- or PTHrP-induced cAMP signaling responses for both mutants, as compared to WT-PTH1R. Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones. Our findings demonstrate a new skeletal phenotype associated with PTH1R variants and suggest that helix 8 of the receptor contributes to PTH1R expression and/or signaling during bone development. The parathyroid hormone receptor 1 (PTH1R) is essential for calcium signaling and bone development. Changes in the PTH1R gene and/or protein affect its ability to function properly thus leading to disease. In a large family and an unrelated case, we identified changes in the PTH1R gene as the cause of short fingers and toes (Brachydactyly type E; BDE), short stature, and dental abnormalities, which is novel for PTH1R variants. Through experiments in cells and mice, we showed that the altered PTH1R protein affects cellular signaling and function, and leads to abnormal bone development. This work improves the understanding of PTH1R-related signaling and disease.

Brachydactyly type E (BDE) is characterized by variable shortening of metacarpals or metatarsals, often involving phalanges. It may occur as an isolated anomaly or as part of congenital syndromes. With advancements in molecular diagnostic technologies, how genetic testing enhances the precise diagnosis of BDE remains unclear. Our aims were to establish an algorithm for molecular genetic diagnostics in Chinese children with BDE and to explore the phenotype-genotype correlations of Chinese patients with BDE. We reviewed left-hand wrist X-rays from children visiting Children's Hospital of Soochow University (Jun 2021-Dec 2023). From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected. Whole-exome sequencing (WES) with copy number variation (CNV) analysis was performed on 60 patients and their parents. Sanger sequencing was used to validate single nucleotide variants (SNV) and indels. Causative variants were found in 19 patients. SNVs and indels affecting 10 genes were identified in 15 patients, and CNVs in four. GNAS mutations were the leading cause (four cases), followed by EXT1 and ACAN defects. The diagnostic yield was 19.1% in patients with isolated brachydactyly; 75% in patients with brachydactyly combined with short stature; 77.8% in patients with brachydactyly combined with facial dysmorphism; 83.3% in patients with brachydactyly combined with intellectual disability. Through comprehensive evaluation of genotype-phenotype correlations, we propose a diagnostic algorithm for precise molecular diagnosis in Chinese children with BDE.

Hypertension is a growing concern worldwide, with increasing prevalence rates in both children and adults. Most cases of hypertension are multifactorial, with various genetic, environmental, socioeconomic, and lifestyle influences. However, monogenic hypertension, a blanket term for a group of rare hypertensive disorders, is caused by single-gene mutations that are typically inherited in an autosomal dominant fashion, and ultimately disrupt normal blood pressure regulation in the kidney or adrenal gland. Being able to recognize and understand the pathophysiology of these rare disorders is critical for properly diagnosing hypertension, particularly in children and young adults, as treating each form of monogenic hypertension requires specific and targeted treatment approaches. A scoping literature review was conducted on the available knowledge regarding each of the disorders currently categorized as forms of monogenic hypertension. This narrative review serves to highlight the epidemiology, pathophysiology, clinical presentation, recent case reports, and most current methods of evaluation and treatment for familial hyperaldosteronism types 1-4, Gordon syndrome. Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, Geller syndrome, hereditary syndromes related to pheochromocytomas and paragangliomas, and brachydactyly type E. Recent and future advances in genetic analysis techniques will further enhance the diagnosis and early management of these disorders, preventing the consequences of uncontrolled hypertension.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.