TSH Elevations as the First Laboratory Evidence for Pseudohypoparathyroidism Type Ib (PHP-Ib)

Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William E.; Koscielniak, Nikolas; Kottler, Marie‐Laure; Agretti, Patrizia; Marco, Giuseppina De; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

doi:10.1002/jbmr.2408

Cited by 30 publications

(34 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…By contrast, patients with PHP1B show abnormal patterns of methylation in the DMRs associated with the GNAS complex locus 45,47,[86][87][88]101,143,[151][152][153][154] . A methylation defect can be classified as partial or complete and can affect one or multiple DMRs within 20q13 (reF.…”

Section: Molecular Diagnosismentioning

confidence: 92%

“…Subsequent analyses have demonstrated that some patients with PHP1B display additional features that overlap with PHP1A. As in PHP1A, PTH resistance might not be present at birth and develops only over time [44][45][46][47][48][49][50] . TSH resistance and patterns of excessive intrauterine growth or weight gain at birth or during early infancy and childhood have been described 44,51,52 .…”

Section: Methodsmentioning

confidence: 99%

“…GNAS shows differential methylation at four distinct DMRs: one paternally methylated-DMR (GNAS-NESP:TSS-DMR) and three maternally methylated-DMRs (GNAS-AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS-DMR, according to the current nomenclature 156 ). Loss of methylation at GNAS A/B:TSS-DMR is detected in all patients with PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] .…”

Section: Molecular Diagnosismentioning

confidence: 97%

“…Early-onset hypothyroidism Congenital hypothyroidism of any cause 46,47 Small thyroid and TSH moderately elevated; no other associated features TSH resistance due to mutations in the TSH receptor 276 Small thyroid and TSH moderately elevated; no other associated features…”

Section: Evolution Of Php Classificationmentioning

confidence: 99%

“…If a female carries the STX16 or NESP/AS deletion, each of her descendants has a 50% risk of inheriting the genetic defect, and if the descendant inherits the defect, he or she will present with a methylation defect affecting only GNAS A/B:TSS-DMR or the complete GNAS locus (depending on the inherited deletion) 18 . In both cases, the descendant will develop PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] . Although translocations of chromosome 20 resulting in UPD(20)pat are very rare, parental karyotyping is recommended to establish the risk of recurrence.…”

Section: Genetic Counsellingmentioning

confidence: 99%

See 4 more Smart Citations

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

View full text Add to dashboard Cite

Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency , hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

show abstract

Section: Molecular Diagnosismentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Molecular Diagnosismentioning

confidence: 97%

Section: Evolution Of Php Classificationmentioning

confidence: 99%

Section: Genetic Counsellingmentioning

confidence: 99%

See 3 more Smart Citations

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

View full text Add to dashboard Cite

show abstract

Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion

Lange

Stuart

Luijt

et al. 2016

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Pseudohypoparathyroidism (PHP) is a genetic disorder with resistance to parathyroid hormone (PTH) as most important feature. Main subtypes of the disease are pseudohypoparathyroidism 1b (PHP1b) and pseudohypoparathyroidism 1a (PHP1a). PHP1b is characterized by PTH resistance of the renal cortex due to reduced activity of the stimulatory G protein α subunit (Gsα) of the PTH receptor. In addition to resistance to PTH, PHP1a patients also lack sensitivity for other hormones that signal their actions through G protein-coupled receptors and display physical features of Albright hereditary osteodystrophy (AHO), which is not classically seen in PHP1b patients. PHP1a is caused by heterozygous loss-of-function mutations in maternally inherited GNAS exons 1-13, which encode Gsα. PHP1b is often caused by deletion of the STX16 gene, which is thought to have an important role in controlling the methylation and thus imprinting at part of the GNAS locus. Here we present a patient with PHP1b caused by the previously described recurrent 3-kb STX16 deletion. The patient's first symptoms were macrosomia, early onset obesity, and macrocephaly. Since this is an atypical but previously described rare presentation of PHP1b, we reemphasize STX16 deletions and PHP1b as a rare cause for early onset obesity and macrosomia. © 2016 Wiley Periodicals, Inc.

show abstract

A Distinct Variant of Pseudohypoparathyroidism (PHP) First Characterized Some 41 Years Ago Is Caused by the 3‐kbSTX16 Deletion

et al. 2021

Self Cite

View full text Add to dashboard Cite

In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

show abstract

TSH Elevations as the First Laboratory Evidence for Pseudohypoparathyroidism Type Ib (PHP-Ib)

Cited by 30 publications

References 41 publications

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion

A Distinct Variant of Pseudohypoparathyroidism (PHP) First Characterized Some 41 Years Ago Is Caused by the 3‐kbSTX16 Deletion

Contact Info

Product

Resources

About