-
Current Osteoporosis Reports Jun 2023Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia,... (Review)
Review
PURPOSE OF REVIEW
Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. PHP is divided into several subtypes with different yet overlapping phenotypes. Research on the bone status in patients with PHP is sparse and has yielded inconsistent results. This review was performed to summarize the current knowledge on the bone phenotypes and possible mechanisms of PHP.
RECENT FINDINGS
Patients with PHP exhibit highly variable bone phenotypes and increased concentrations of bone turnover markers. Long-standing elevation of the parathyroid hormone concentration may lead to hyperparathyroid bone diseases, including rickets and osteitis fibrosa. Compared with normal controls, patients with PHP may exhibit similar, increased, or decreased bone mineral density. Higher bone mineral density has been found in patients with PHP type 1A than in normal controls, whereas decreased bone mass, osteosclerosis, and osteitis fibrosa cystica have been reported in patients with PHP type 1B, indicating more variable bone phenotypes in PHP type 1B. Bone tissues show partial sensitivity to parathyroid hormone in patients with PHP, leading to heterogeneous reactions to parathyroid hormone in different individuals and even in different regions of bone tissues in the same individual. Regions rich in cancellous bone are more sensitive and show more obvious improvement after therapy. Active vitamin D and calcium can significantly improve abnormal bone metabolism in patients with PHP.
Topics: Humans; Bone and Bones; Pseudohypoparathyroidism; Parathyroid Hormone; Bone Diseases; Phenotype; GTP-Binding Protein alpha Subunits, Gs; Chromogranins
PubMed: 37014531
DOI: 10.1007/s11914-023-00787-6 -
Journal of Pediatric Endocrinology &... Feb 2023The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that... (Review)
Review
The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that affect the developing skeleton. Progress has been facilitated through advances in both technology and biology and this paper provides a brief description of some but not all of the key findings, including identification of the calcium sensing receptor and the polypeptides parathyroid hormone and parathyroid hormone-related protein as well as their shared receptor and signal generating pathways; the elucidation of vitamin D metabolism and actions; discovery of fibroblast growth factor 23 (FGF23), the sodium-phosphate co-transporters and the other components that regulate phosphate metabolism. Moreover, the past half-century of research has led to the delineation of the molecular bases for genetic forms of hypoparathyroidism, pseudohypoparathyroidism, and primary hyperparathyroidism as well as the determination of the genetic causes of osteogenesis imperfecta, osteopetrosis, hypophosphatasia, and other disorders of mineral/bone homeostasis. During the next decade we expect that many of these fundamental discoveries will lead to the development of innovative treatments that will improve the lives of children with these disorders.
Topics: Child; Adolescent; Humans; Bone and Bones; Parathyroid Hormone; Osteogenesis Imperfecta; Hypophosphatasia; Phosphates; Fibroblast Growth Factors; Calcium; Vitamin D
PubMed: 36636022
DOI: 10.1515/jpem-2022-0624 -
Neuro-Chirurgie Nov 2019Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic... (Review)
Review
INTRODUCTION
Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder.
MATERIAL AND METHODS
A review of the literature on metabolic forms of craniosynostosis was performed.
RESULTS
The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe.
CONCLUSION
The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.
Topics: Bone Diseases, Metabolic; Cranial Sutures; Craniosynostoses; Humans; Minerals; Mucopolysaccharidoses; Rickets
PubMed: 31562881
DOI: 10.1016/j.neuchi.2019.09.008 -
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 -
Current Obesity Reports Jun 2024Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital... (Review)
Review
Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. PURPOSE OF REVIEW: To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare condition with high phenotypic variability and genetic heterogeneity. The following syndromes are presented in this review: Prader-Willi, Bardet-Biedl, Pseudohypoparathyroidism, Alström, Smith-Magenis, Cohen, Temple, 1p36 deletion, 16p11.2 microdeletion, Kleefstra, SIM1-related, Börjeson-Forssman-Lehmann, WAGRO, Carpenter, MORM, and MYT1L-related syndromes. RECENT FINDINGS: There are three main groups of mechanisms for syndromic obesity: imprinting, transcriptional activity regulation, and cellular cilia function. For molecular diagnostic, methods of genome-wide investigation should be prioritized over sequencing of panels of syndromic obesity genes. In addition, we present novel syndromic conditions that need further delineation, but evidences suggest they have a higher frequency of obesity. The etiology of syndromic obesity tends to be linked to disrupted neurodevelopment (central) and is associated with a diversity of genes and biological pathways. In the genetic investigation of individuals with syndromic obesity, the possibility that the etiology of the syndromic condition is independent of obesity should be considered. The accurate genetic diagnosis impacts medical management, treatment, and prognosis, and allows proper genetic counseling.
Topics: Humans; Obesity; Intellectual Disability; Syndrome; Phenotype; Bardet-Biedl Syndrome; Prader-Willi Syndrome; Developmental Disabilities; Alstrom Syndrome
PubMed: 38277088
DOI: 10.1007/s13679-023-00543-y -
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