User demographics and real-world use of the digital diabetes companion app dibi: a retrospective analysis.

Pseudohypoparathyroidism (PHP), initially described by Fuller Albright and colleagues, is a disorder characterized by resistance to parathyroid hormone (PTH). PHP has been classified into type I and type II according to the nature of nephrogenous response to PTH administration (, ). PHP type I, where PTH-induced elevation of both urinary cAMP and phosphate is blunted, results from defects in the imprinted that diminish the expression or the activity of its major product, the stimulatory G protein alpha-subunit (Gsα) (, ). PHP type I is further subdivided into several subtypes based on molecular mechanisms, inheritance patterns, and DNA methylation abnormalities: PHP type 1A (PHP1A), PHP type 1B (PHP1B), and pseudopseudohypoparathyroidism (PPHP) (). Gsα is a signaling protein that mediates the actions of numerous endogenous ligands via cAMP generation. While it is biallelically expressed in many tissues, the paternal Gsα allele is silenced in a number of tissues including the proximal renal tubules, pituitary, thyroid gland, and certain parts of the hypothalamus, making the maternal allele the predominant source of Gsα (, ). Consequently, genetic or epigenetic defects affecting the maternal allele led to severely impaired Gsα-dependent receptor signaling in these tissues (). Caused by heterozygous inactivating mutations within the Gsα-coding exons of the maternal allele, PHP1A is characterized by resistance to multiple hormones, including PTH, TSH, gonadotropins, and GHRH, as well as Albright hereditary osteodystrophy (AHO), which encompasses short stature, obesity, round face, brachydactyly, heterotopic subcutaneous ossifications, and intellectual disability (). The patients often develop obesity within the first two years of life (). The severity of cognitive impairment is heterogeneous, with 30% showing normal cognitive development (, ). PTH resistance is the most common form of hormone resistance and is usually identified in childhood (, ). Evidence of TSH resistance can be detected during the neonatal period. Inactivating variants affecting Gsα-coding exons of the paternal allele cause PPHP, which manifests as AHO phenotype, without hormone resistance (). Thus, AHO features are present in patients with Gsα-coding mutations regardless of the parental origin. However, studies suggest that obesity and intellectual disability are features that are primarily found in PHP1A rather than PPHP cases (, ). On the other hand, PHP1B, is caused by epigenetic defects (aberrant methylation) of the maternal allele, with all reported cases showing a loss of methylation at the A/B differentially methylated region in the absence or presence of additional methylation abnormalities in this locus (, ). The A/B loss of methylation results in the silencing of both Gsα alleles in those tissues in which the paternal Gsα allele is normally silenced, thereby leading to severe Gsα deficiency. The recurrent genetic defect, particularly found in familial cases, is a maternal microdeletion with the neighboring gene (), which disrupts a long-range enhancer of one of transcripts that is crucial for maintaining A/B methylation in the early embryo (). PHP1B patients present with isolated PTH resistance, with mild TSH resistance manifesting in a substantial number of cases. Typically, the hormone resistance is not accompanied by AHO phenotype, although several cases with mild brachydactyly or other skeletal manifestations have been observed ().