-
Best Practice & Research. Clinical... Apr 2018Metabolic disorders deriving from the non-responsiveness of target organs to hormones, which manifest clinically similar to the deficiency of a given hormone itself,... (Review)
Review
Metabolic disorders deriving from the non-responsiveness of target organs to hormones, which manifest clinically similar to the deficiency of a given hormone itself, derive from molecular alterations affecting specific hormone receptors. Pseudohypoparathyroidism (PHP) and related disorders exemplify an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of cAMP signaling pathway, or, as more recently described, of downstream effector proteins of the same pathway, such as PKA regulatory subunit 1A (R1A) and phosphodyestarase type 4D (PDE4D). In this group of diseases, resistance to hormones such as PTH, TSH, gonadotropins and GHRH may be variably present, so that the clinical and molecular overlap among these different but related disorders represents a challenge for endocrinologists as to differential diagnosis and genetic counseling. This review will describe the presenting features of multiple resistance in PHP and related disorders, focusing on both our current understanding and future challenges.
Topics: Drug Resistance; Endocrine System Diseases; Hormones; Humans; Parathyroid Hormone; Pseudohypoparathyroidism; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 29678282
DOI: 10.1016/j.beem.2018.01.002 -
European Journal of Endocrinology Dec 2023Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups...
OBJECTIVE
Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups according to etiologies and methylation defect patterns of the DMRs. The aim of this study was to clarify the clinical characteristics of each group.
DESIGN
Comprehensive molecular analyses consisting of methylation, copy number, and microsatellite analyses.
METHODS
Eighty-four patients with PHP1B were included in this study. We classified them into 5 groups, namely, autosomal dominant inheritance-PHP1B (Group 1, G1), sporadic-PHP1B (G2), and atypical-PHP1B (G3-G5), based on the methylation defect patterns in 4 DMRs on the GNAS locus and etiologies and evaluated the clinical findings in each group and compared them among the groups.
RESULTS
G2 had the youngest age and the highest serum intact parathyroid hormone levels among the 5 groups at the time of diagnosis. The most common symptoms at the time of diagnosis were tetany in G1, and seizures or loss of consciousness in G2. Albright's hereditary osteodystrophy and PHP-suggestive features were most frequently observed in the G2 proband. Nine patients had neurodevelopmental disorders (NDs) consisting of mild to borderline intellectual disability and/or developmental delay. There were no significant correlations between the average methylation ratios of 7 CpG sites in the GNAS-A/B:TSS-DMR and hormonal and biochemical findings.
CONCLUSION
This study revealed the differences in some clinical characteristics, particularly clinical features, and ages at the time of diagnosis between G2 and other groups and detailed NDs observed in some patients with PHP1B.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Pseudohypoparathyroidism; Family; DNA Methylation
PubMed: 38039118
DOI: 10.1093/ejendo/lvad163 -
Clinical Endocrinology Oct 2022Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary... (Review)
Review
Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%-10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium-related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.
Topics: Calcium; Calcium, Dietary; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Phenotype; Receptors, Calcium-Sensing
PubMed: 34935164
DOI: 10.1111/cen.14644 -
The Journal of Clinical Endocrinology... Jul 2021Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of...
CONTEXT
Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH.
OBJECTIVE
To describe a cohort of 26 patients with PHP followed in a single tertiary center.
METHODS
Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002.
RESULTS
Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium-phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort.
CONCLUSION
Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.
Topics: Adolescent; Adult; Brain Diseases; Calcinosis; Cerebral Cortex; Child; Child, Preschool; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Humans; Kidney; Kidney Diseases; Middle Aged; Mutation; Pseudohypoparathyroidism; Ultrasonography; Young Adult
PubMed: 33780542
DOI: 10.1210/clinem/dgab208 -
Calcified Tissue International Jan 2021Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia... (Review)
Review
Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.
Topics: Calcinosis; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperostosis, Cortical, Congenital; Hyperphosphatemia; Male; Mutation
PubMed: 31965220
DOI: 10.1007/s00223-020-00659-6 -
Anales de Pediatria Aug 2023Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the...
Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the presence of hyperphosphatemia and hypocalcaemia of varying severity. Early-onset obesity is a feature of PHP type 1A. This article discusses the need to establish uniform criteria to guide the nutritional management of patients with PHP. A decrease in energy expenditure calls for an adjustment of the energy content of the diet. Reducing the intake of foods rich in inorganic phosphorus helps to manage hyperphosphataemia. Targeted nutrition should be part of the treatment plan of children and adolescents with PHP, since it contributes to modulating the calcium and phosphorus metabolism imbalances characteristic of these patients.
Topics: Adolescent; Child; Humans; Pseudohypoparathyroidism; Parathyroid Hormone; Nutritional Status; Phosphorus
PubMed: 37481364
DOI: 10.1016/j.anpede.2023.05.007 -
Best Practice & Research. Clinical... Dec 2018Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target... (Review)
Review
Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations similar to the deficiency of the hormone itself. Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory subunit 1A and the phosphodiesterase type 4D. The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so that a new nomenclature and classification has been recently proposed grouping these disorders under the term "inactivating PTH/PTHrP signaling disorder" (iPPSD). This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous but closely related diseases.
Topics: Bone Diseases, Metabolic; Drug Resistance; Dysostoses; Endocrine System Diseases; GTP-Binding Protein alpha Subunits, Gs; Humans; Intellectual Disability; Ossification, Heterotopic; Osteochondrodysplasias; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Signal Transduction; Skin Diseases, Genetic; Syndrome
PubMed: 30665554
DOI: 10.1016/j.beem.2018.09.008 -
Human Mutation Jan 2015Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features... (Review)
Review
Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright's hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype-phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.
Topics: Animals; Bone Diseases, Metabolic; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Mutation; Ossification, Heterotopic; Pseudohypoparathyroidism; Skin Diseases, Genetic
PubMed: 25219572
DOI: 10.1002/humu.22696 -
Child's Nervous System : ChNS :... Dec 2023The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a... (Review)
Review
PURPOSE
The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a review of the literature in an effort to understand management for this rare entity.
METHODS
Retrospective review of the electronic medical record database was performed to identify patients with primary metabolic bone disorders who underwent craniosynostosis surgery between 2011 and 2022 at a quaternary referral pediatric hospital. Literature review was conducted for primary metabolic bone disorders associated with craniosynostosis.
RESULTS
Ten patients were identified, 6 of whom were male. The most common bone disorders were hypophosphatemic rickets (n = 2) and pseudohypoparathyroidism (n = 2). The median age at diagnosis of metabolic bone disorder was 2.02 years (IQR: 0.11-4.26), 2.52 years (IQR: 1.24-3.14) at craniosynostosis diagnosis, and 2.65 years (IQR: 0.91-3.58) at the time of surgery. Sagittal suture was most commonly fused (n = 4), followed by multi-suture craniosynostosis (n = 3). Other imaging findings included Chiari (n = 1), hydrocephalus (n = 1), and concurrent Chiari and hydrocephalus (n = 1). All patients underwent surgery for craniosynostosis, with the most common operation being bifronto-orbital advancement (n = 4). A total of 5 patients underwent reoperation, 3 of which were planned second-stage surgeries and 2 of whom had craniosynostosis recurrence.
CONCLUSIONS
We advocate screening for suture abnormalities in children with primary metabolic bone disorders. While cranial vault remodeling is not associated with a high rate of postoperative complications in this patient cohort, craniosynostosis recurrences may occur, and parental counseling is recommended.
Topics: Child, Preschool; Female; Humans; Infant; Male; Bone Diseases, Metabolic; Craniosynostoses; Familial Hypophosphatemic Rickets; Hydrocephalus; Retrospective Studies; Skull
PubMed: 37420034
DOI: 10.1007/s00381-023-06059-z -
Journal of Clinical Research in... Mar 2020Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive... (Review)
Review
Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive development, metabolism and cancer predisposition. Aberrant expression of imprinted genes can be achieved through different mechanisms, classified into epigenetic - if not involving DNA sequence change - or genetic in the case of altered genomic sequence. Despite the underlying mechanism, the phenotype depends on the parental allele affected and opposite phenotypes may result depending on the involvement of the maternal or the paternal chromosome. Imprinting disorders are largely underdiagnosed because of the broad range of clinical signs, the overlap of presentation among different disorders, the presence of mild phenotypes, the mitigation of the phenotype with age and the limited availability of molecular techniques employed for diagnosis. This review briefly illustrates the currently known human imprinting disorders, highlighting endocrinological aspects of pediatric interest.
Topics: Abnormalities, Multiple; Child; Diabetes Mellitus; Genomic Imprinting; Humans; Infant, Newborn, Diseases; Intellectual Disability; Pseudohypoparathyroidism; Puberty, Precocious; Syndrome; Uniparental Disomy
PubMed: 30968677
DOI: 10.4274/jcrpe.galenos.2019.2018.0249