Multiple hormone resistance and alterations of G-protein-coupled receptors signaling Mantovani, Giovanna; Elli, Francesca Marta
Baillière's best practice and research in clinical endocrinology and metabolism/Baillière's best practice & research. Clinical endocrinology & metabolism,
April 2018, 2018-04-00, Letnik:
32, Številka:
2
Journal Article
Recenzirano
Odprti dostop
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.
Context:
The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic ...alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects.
Objective:
The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects.
Design:
With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain.
Results:
Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A/B:TSS-DMR. Multihormone resistance with no Albright's hereditary osteodystrophy (AHO) signs (61/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18/407, 4%) and progressive osseous heteroplasia (7/407, 2%) were exclusively caused by point mutations.
Conclusion:
With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.
Pseudohypoparathyroidism is caused by molecular alterations within or upstream of GNAS. We have established the prevalence of various genetic and epigenetic lesions in European PHP-affected patients.
Hypothyroidism associated with parathyroid disorders Mantovani, Giovanna; Elli Francesca, Marta; Corbetta, Sabrina, MD, PhD
Best Practice & Research Clinical Endocrinology & Metabolism,
03/2017, Letnik:
31, Številka:
2
Journal Article
Recenzirano
Abstract Hypothyroidism may occur in association with congenital parathyroid disorders determining parathyroid hormone insufficiency, which is characterized by hypocalcemia and concomitant ...inappropriately low secretion of parathormone (PTH). The association is often due to loss of function of genes common to thyroid and parathyroid glands embryonic development. Hypothyroidism associated with hypoparathyroidism is generally mild and not associated with goiter; moreover, it is usually part of a multisystemic involvement not restricted to endocrine function as occurs in patients with 22q11 microdeletion/DiGeorge syndrome, the most frequent disorders. Hypothyroidism and hypoparathyroidism may also follow endocrine glands’ damages due to autoimmunity or chronic iron overload in thalassemic disorders, both genetically determined conditions. Finally, besides PTH deficiency, hypocalcemia can be due to PTH resistance in pseudohypoparathyroidism; when hormone resistance is generalized, patients can suffer from hypothyroidism due to TSH resistance. In evaluating patients with hypothyroidism and hypocalcemia, physical examination and clinical history are essential to drive the diagnostic process, while routine genetic screening is not recommended.
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.
GNAS is a complex gene that encodes Gsα, a signaling protein that triggers a complex network of pathways. Heterozygous inactivating mutations in Gsα-coding GNAS exons cause hormonal resistance; on ...the contrary, activating mutations in Gsα result in constitutive cAMP stimulation. Recent research has described a clinical condition characterized by both gain and loss of Gsα function, due to a heterozygous de novo variant of the maternal GNAS allele.
We describe a girl with a complex combination of clinical signs and a new heterozygous GNAS variant. For the molecular analysis of GNAS gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples. In silico analysis was performed to predict the possible in vivo effect of the detected novel genetic variant. The activity of Gsα protein was in vitro analyzed from samples of erythrocyte membranes, recovered from heparinized blood samples.
We found a new heterozygous missense c.166A > T-(p.Ile56Phe) GNAS variant in exon 2, inherited from the mother that determined a reduced activity of 50% of Gsα protein function. The analysis of her parents showed a 20-25% reduction in Gsα protein activity in the mother and a normal function in the father. Clinically our patient presented a multisystemic disorder characterized by hyponatremia compatible with a nephrogenic syndrome of inappropriate antidiuresis, subclinical hyperthyroidism, subclinical hypercortisolism, precocious thelarche and pubarche and congenital bone abnormalities.
This is the first time that the new variant c.166A > T (p.Ile56Phe) on exon 2 of GNAS gene, originated on maternal allele, has been described as probable cause of a multisystemic disorder. Although the mutation is associated with a reduced activity of the function of Gsα protein, this unusual phenotype on the contrary suggests a mild functional gain.
The dysregulation of cell fate toward osteoprecursor cells associated with most
-based disorders may lead to episodic
extraskeletal or ectopic bone formation in subcutaneous tissues. The bony lesion ...distribution suggests the involvement of abnormal differentiation of mesenchymal stem cells (MSCs) and/or more committed precursor cells. Data from transgenic mice support the concept that
is a crucial factor in regulating lineage switching between osteoblasts (OBs) and adipocyte fates. The mosaic nature of heterotopic bone lesions suggests that
genetic defects provide a sensitized background for ectopic osteodifferentiation, but the underlying molecular mechanism remains largely unknown.
The effect of
silencing in the presence and/or absence of osteoblastic stimuli was evaluated in the human L88/5 MSC line during osteodifferentiation. A comparison of the data obtained with data coming from a bony lesion from a
-mutated patient was also provided.
Our study adds some dowels to the current fragmented notions about the role of
during osteoblastic differentiation, such as the premature transition of immature OBs into osteocytes and the characterization of the differences in the deposed bone matrix.
We demonstrated that our cell model partially replicates the
behavior results, resulting in an applicable human model to elucidate the pathophysiology of ectopic bone formation in
-based disorders.
Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine neoplasm that may spread to lymph nodes before the primary tumor is diagnosed; moreover, distant metastases are already present in ...about 10% of patients at diagnosis. Serum calcitonin (Ctn) usually reflects the spread of disease, thus orienting the extent of surgery and predicting the possibility of biochemical remission. Tumor size and vascular invasion are important prognostic factors, but little is known on the relationship between other histopathological features, such as the presence of a tumor capsule, and long term outcome of MTC.
To evaluate the prevalence of encapsulated tumors among MTCs and the association of tumor capsule with a favorable outcome after surgery.
A retrospective observational single-center study was conducted together with a narrative review of the available literature.
Among 44 patients (27 female, 17 male; median age: 56 years) with MTC (6 hereditary, 37 sporadic) followed up at our center in the last four years (median follow-up: 29.2 months), seven (15.9%) showed an encapsulated tumor at histology and a clinical remission after surgery. None of them had nodal metastases and median preoperative Ctn (398 pg/mL, IQR 126.5-7336) did not differ significantly from that of the 14 patients (31.8%) with persistent disease after surgery (787 pg/mL, IQR 340.5-2905.5; p=0.633), although their tumor size was significantly higher (median 33 mm versus 16 mm respectively, p=0.036). Among patients with preoperative Ctn levels above 500 pg/mL (n=11), only two (18.2%) showed undetectable Ctn levels during follow-up, both having an encapsulated MTC (OR 0.000, p=0.02). Notably, they were two similar cases of large MTC (> 3 cm) with extensive hyalinization and calcification, associated with very high Ctn levels (> 13'500 and 1'100 pg/mL, respectively) but no nodal nor distant metastases, in complete remission after surgery although one of them carried the aggressive M918T somatic
mutation.
MTC rarely shows a tumor capsule, which seems to correlate with a better prognosis and absence of nodal metastases, regardless of
or
mutational status. Among encapsulated MTCs (E-MTC), Ctn levels and tumor size are not predictive of persistence of disease after surgery.
PTH resistance Mantovani, Giovanna; Elli, Francesca Marta
Molecular and cellular endocrinology,
07/2021, Letnik:
531
Journal Article
Recenzirano
Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from PTH deficiency ...(hypoparathyroidism), excess (hyperparathyroidism) and resistance (pseudohypoparathyroidism, PHP). Pseudohypoparathyroidism was historically classified into subtypes according to the presence or not of inherited PTH resistance associated or not with features of Albright's hereditary osteodystrophy and deep and progressive ectopic ossifications. The growing knowledge on the PTH/PTHrP signaling pathway showed that molecular defects affecting different members of this pathway determined distinct, yet clinically related disorders, leading to the proposal of a new nomenclature and classification encompassing all disorders, collectively termed inactivating PTH/PTHrP signaling disorders (iPPSD).
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