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1.
Orphanet J Rare Dis ; 16(1): 421, 2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627337

RESUMO

BACKGROUND: Hypoparathyroidism (HypoPT) or pseudo-hypoparathyroidism (pseudo-HypoPT) during pregnancy may cause maternal and fetal/neonatal complications. In this regard, only a few case reports or case series of pregnant or lactating women have been published. The purpose of this study was to describe clinical and biochemical course, pharmacological management, and potential adverse events during pregnancy and post-partum in pregnant women with HypoPT or pseudo-HypoPT. This was a retrospective, observational, multicenter, study involving nine Italian referral centers for endocrine diseases affiliated with the Italian Society of Endocrinology and involved in "Hypoparathyroidism Working Group". RESULTS: This study identified a cohort of 28 women (followed between 2005 and 2018) with HypoPT (n = 25, 84% postsurgical, 16% idiopathic/autoimmune) and pseudo-HypoPT (n = 3). In HypoPT women, the mean calcium carbonate dose tended to increase gradually from the first to third trimester (+ 12.6%) in pregnancy. This average increase in the third trimester was significantly greater compared to the pre-pregnancy period (p value = 0.03). However, analyzing the individual cases, in 44% the mean calcium dosage remained unchanged throughout gestation. Mean calcitriol doses tended to increase during pregnancy, with a statistically significant increase between the third trimester and the pre-pregnancy period (p value = 0.02). Nevertheless, analyzing the individual cases, in the third trimester most women with HypoPT (64%) maintained the same dosage of calcitriol compared to the first trimester. Both mean calcium carbonate and calcitriol doses tended to decrease from the third trimester to the post-partum six months. Most identified women (~ 70%) did not display maternal complications and (~ 90%) maintained mean serum albumin-corrected total calcium levels within the low-to-mid normal reference range (8.5 ± 0.8 mg/dl) during pregnancy. The main complications related to pregnancy period included: preterm birth (n = 3 HypoPT women), and history of miscarriages (n = 6 HypoPT women and n = 2 pseudo-HypoPT women). CONCLUSION: This study shows that mean serum albumin-corrected total calcium levels were carefully monitored during pregnancy and post-pregnancy, with limited evaluation of other biochemical parameters, such as serum phosphate, 24 h urinary calcium, 25-OH vitamin D, and creatinine clearance. To avoid complications in mothers affected by (HypoPT) or (pseudo-HypoPT) and offspring, intense biochemical, clinical and pharmacological monitoring during pregnancy and breastfeeding is highly recommended.


Assuntos
Hipoparatireoidismo , Nascimento Prematuro , Pseudo-Hipoparatireoidismo , Feminino , Humanos , Hipoparatireoidismo/tratamento farmacológico , Recém-Nascido , Itália , Lactação , Gravidez
3.
Clin Endocrinol (Oxf) ; 95(2): 277-285, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33961300

RESUMO

OBJECTIVE: Bone responsiveness to parathyroid hormone (PTH) in different subtypes of pseudohypoparathyroidism type 1 (PHP1) remains controversial. We aimed to investigate this phenomenon using bone turnover markers (BTMs) in a large cohort of PHP1 patients. DESIGN: Retrospective study. PATIENTS: Sixty-three PHP1 patients diagnosed by molecular analysis were used as subjects, and 48 sex- and age-matched patients with nonsurgical hypoparathyroidism (NS-HP) were used for comparison. MEASUREMENTS: Bone turnover markers, alkaline phosphatase (ALP), C-terminal telopeptide of type I collagen (ß-CTX) and related parameters in PHP1 were compared among different subtypes and with NS-HP. RESULTS: Among all the PHP1 patients (15 PHP1A, 14 familial 1B and 34 sporadic 1B), 23.8% had elevated baseline BTM levels. No significant difference was found in the ß-CTX levels among different subtypes. The ß-CTX level was positively correlated with the PTH level for all PHP1, PHP1B and PHP1A patients (B = 0.001, 0.001 and 0.004, respectively; all p < .05). The BTM levels of PHP1 patients were significantly higher than those of NS-HP patients (ß-CTX: 0.56 ng/ml vs. 0.20 ng/ml, p = .001; ALP: 105 U/L vs. 72 U/L, p = .001). The serum ß-CTX levels in different PHP1 subtypes were all significantly higher than those in NS-HP patients in adults. Among the 22 followed up patients, changes in BTMs were associated with changes in PTH (ß-CTX: r = .507, p = .023; ALP: r = .475, p = .034). CONCLUSIONS: Bone tissues respond to PTH in different PHP1 subtypes, and it is reasonable to monitor and normalize PTH and BTMs in addition to the serum and urinary calcium levels in the follow-up of PHP1 patients.


Assuntos
Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo , Adulto , Biomarcadores , Remodelação Óssea , Colágeno Tipo I , Humanos , Estudos Retrospectivos
4.
J Pediatr Endocrinol Metab ; 34(4): 531-534, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33818044

RESUMO

We present an unusual case of SHOX deficiency associated with Léri-Weill dyschondrosteosis (LWD), Hashimoto's thyroiditis and pseudohypoparathyroidism 1B in a young woman. To our knowledge, this is the first ever report of these disorders coexisting. At the age of nine years, the proband was diagnosed of hypothyroidism due to Hashimoto's thyroiditis, and developed biochemical abnormalities consistent with hyperphosphatemia, mild hypocalcemia and elevated parathyroid hormone without any clinical symptoms except short stature. Replacement therapy with levothyroxine, calcium and alphacalcidol was initiated. The diagnosis of pseudohypoparathyroidism 1B was confirmed at the age of 17.5 years with the demonstration of methylation alteration at the GNAS locus. At the age of 16 years, 3.5 years after her menarche, she presented clear features of LWD. A large deletion of the SHOX gene was confirmed. Family genetic tests were not doable since she was adopted. We discuss the diagnostic challenges of these coexisting rare endocrinopathies.


Assuntos
Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Osteocondrodisplasias/complicações , Osteocondrodisplasias/genética , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/genética , Proteína de Homoeobox de Baixa Estatura/deficiência , Proteína de Homoeobox de Baixa Estatura/genética , Tireoidite Autoimune/complicações , Tireoidite Autoimune/genética , Adolescente , Calcitriol/uso terapêutico , Cálcio/uso terapêutico , Feminino , Deleção de Genes , Testes Genéticos , Deformidades da Mão/diagnóstico por imagem , Deformidades da Mão/genética , Humanos , Lipomatose Simétrica Múltipla/diagnóstico por imagem
5.
Zhonghua Er Ke Za Zhi ; 59(3): 206-211, 2021 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-33657695

RESUMO

Objective: To analyze the patients' clinical and genetic characteristics with pseudohypoparathyroidism (PHP) and investigate the correlation between clinical phenotypes and genotypes. Methods: Twenty PHP patients were ascertained at Children's Hospital Zhejiang University School of Medicine from January 2011 to July 2020. Clinical manifestation, laboratory examination and gene test results were retrospectively analyzed. Results: In these twenty patients, eighteen cases showed resistance to parathyroid hormone (PTH) and thirteen cases had Albright's hereditary osteodystrophy (AHO) phenotype. Gene abnormalities were found in all the twenty PHP patients, which included seven patients with GNAS gene variations (six frameshifts and one missense) and thirteen patients with GNAS gene methylation defects. Moreover, twelve children with both PTH resistance and AHO phenotype were clinically diagnosed as PHP-Ⅰa, meanwhile, seven carried GNAS variations and five had methylation abnormalities with a correct diagnosis of PHP-Ⅰb. Conclusions: Patients with AHO phenotype and PTH resistance may have a high genetic diagnosis rate. Because PHP-Ⅰb clinical phenotype may be similar to PHP-Ⅰa, early genetic detection is required for the differential diagnosis. In addition, children without PTH resistance should also be followed up regularly, which may help the early diagnosis.


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , Criança , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Fenótipo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Estudos Retrospectivos
6.
J Clin Endocrinol Metab ; 106(8): e3005-e3020, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33780542

RESUMO

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.


Assuntos
Encefalopatias/genética , Calcinose/genética , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Nefropatias/genética , Mutação , Pseudo-Hipoparatireoidismo/genética , Adolescente , Adulto , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Criança , Pré-Escolar , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Nefropatias/diagnóstico por imagem , Nefropatias/patologia , Pessoa de Meia-Idade , Pseudo-Hipoparatireoidismo/diagnóstico por imagem , Pseudo-Hipoparatireoidismo/patologia , Ultrassonografia , Adulto Jovem
7.
Ital J Pediatr ; 47(1): 48, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663571

RESUMO

BACKGROUND: Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies. METHODS: Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice. RESULTS: In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism. CONCLUSIONS: The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.


Assuntos
Procedimentos Clínicos , Padrões de Prática Médica/estatística & dados numéricos , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/terapia , Criança , Consenso , Feminino , Seguimentos , Humanos , Itália , Masculino , Pseudo-Hipoparatireoidismo/classificação , Inquéritos e Questionários
8.
J Clin Endocrinol Metab ; 106(9): 2779-2787, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-33677588

RESUMO

CONTEXT: Pseudohypoparathyroidism type 1B (PHP1B), also referred to as inactivating PTH/PTHrP signaling disorder (iPPSD), is characterized by proximal renal tubular resistance to parathyroid hormone (PTH) leading to hypocalcemia, hyperphosphatemia, and elevated PTH values. Autosomal dominant PHP1B (AD-PHP1B) with loss of methylation at the maternal GNAS A/B:TSS-DMR (transcription start site-differentially methylated region) alone can be caused by maternal deletions involving STX16. OBJECTIVE: Characterize a previously not reported AD-PHP1B family with loss of methylation at GNAS A/B:TSS-DMR, but without evidence for a STX16 deletion on the maternal allele and assess GNAS-AS2:TSS-DMR methylation. METHODS: DNA from 24 patients and 10 controls were investigated. AD-PHP1B patients without STX16 deletion from a single family (n = 5), AD-PHP1B patients with STX16 deletion (n = 9), sporPHP1B (n = 10), unaffected controls (n = 10), patUPD20 (n = 1), and matUPD20 (n = 1). Methylation and copy number analyses were performed by pyrosequencing, methylation-sensitive multiplex ligation-dependent probe amplification, and multiplex ligation-dependent probe amplification. RESULTS: Molecular cloning of polymerase chain reaction-amplified, bisulfite-treated genomic DNA from healthy controls revealed evidence for 2 distinct GNAS-AS2:TSS-DMR subdomains, named AS2-1 and AS2-2, which showed 16.0 ±â€…2.3% and 31.0 ±â€…2.2% methylation, respectively. DNA from affected members of a previously not reported AD-PHP1B family without the known genetic defects revealed incomplete loss of methylation at GNAS A/B:TSS-DMR, normal methylation at the 3 well-established maternal and paternal DMRs, and, surprisingly, increased methylation at AS2-1 (32.9 ±â€…3.5%), but not at AS2-2 (30.5 ±â€…2.9%). CONCLUSION: The distinct methylation changes at the novel GNAS-AS2:TSS-DMR will help characterize further different PHP1B/iPPSD3 variants and will guide the search for underlying genetic defects, which may provide novel insights into the mechanisms underlying GNAS methylation.


Assuntos
Cromograninas/genética , Metilação de DNA , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sítio de Iniciação de Transcrição
9.
Calcif Tissue Int ; 108(6): 775-784, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33576839

RESUMO

Hypoparathyroidism (HypoPT) and pseudohypoparathyroidism (PHP) are diseases with abnormal calcium and phosphate homeostasis and low and high PTH levels, respectively. It has been hypothesized that this could dispose to vascular calcifications and thereby perhaps also cardiovascular morbidity. The aim of this study was to assess lower leg arterial calcifications (LLAC) in patients with HypoPT or PHP. Using a cross-sectional design, we measured the LLAC using a high-resolution peripheral quantitative computed tomography (HR-pQCT) scanner in 72 patients with HypoPT and 25 patients with PHP and compared them with findings in 61 controls. LLAC were found in only two (3%) of the controls. Compared to the controls, LLAC were significantly more prevalent in patients with HypoPT (N = 12, [17%], p < 0.01) and PHP (N = 4, [16%], p < 0.04). Compared to the patients without calcifications, patients with calcifications had higher plasma calcium levels and a lower eGFR, as well as they were older and more often males. Plasma phosphate levels and the calcium-phosphate product were not associated with LLAC. In conclusion, we found that HypoPT and PHP are associated with an increased prevalence of vascular calcifications.


Assuntos
Hipoparatireoidismo , Pseudo-Hipoparatireoidismo , Calcificação Vascular , Cálcio , Estudos Transversais , Feminino , Humanos , Hipoparatireoidismo/complicações , Perna (Membro) , Masculino , Hormônio Paratireóideo , Tomografia Computadorizada por Raios X , Calcificação Vascular/diagnóstico por imagem
10.
J Clin Endocrinol Metab ; 106(6): 1541-1552, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33529330

RESUMO

Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright's hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).


Assuntos
Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/genética , Cromograninas/genética , Metilação de DNA , Epigênese Genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Técnicas de Diagnóstico Molecular , Pseudo-Hipoparatireoidismo/diagnóstico
11.
BMC Endocr Disord ; 21(1): 12, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33422028

RESUMO

BACKGROUND: Pseudohypoparathyroidism is a rare genetic disease characterized by hypocalcaemia and hyperphosphataemia due to the defect to the guanine nucleotide-binding protein alpha subunit (GNAS) gene. Patients with pseudoparathyroidism type 1a and 1c could manifest Albright's hereditary osteodystrophy and multiple hormone resistance including gonadotropin and thyroid stimulating hormone. CASE PRESENTATION: Here we report a Chinese man who presented with fatigue, recurrent seizure and Albright's hereditary osteodystrophy. His genetic study revealed a heterozygote mutation in the GNAS gene [NM_000516.4(GNAS): c2787_2788del (p.Val930AspfsTer12)]. After calcium and calcitriol supplement, his seizures achieved partially remission. CONCLUSIONS: We report a case of PHP1a or 1c with a novel frameshift mutation in GNAS gene in a patient presenting with AHO, as well as TSH and partial gonadotropin resistance. This mutation in this case has not been reported in literature and adds to the spectrum of genetic mutations related to PHP.


Assuntos
Cromograninas/genética , Mutação da Fase de Leitura/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Convulsões/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Calcitriol/uso terapêutico , Cálcio/uso terapêutico , Suplementos Nutricionais , Displasia Fibrosa Poliostótica/complicações , Hormônios/sangue , Humanos , Masculino , Mutação , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico por imagem , Recidiva , Convulsões/etiologia , Tireotropina/sangue
12.
J Bone Miner Res ; 36(3): 546-552, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33180333

RESUMO

Pseudohypoparathyroidism type Ib (PHP1B) is characterized by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia, and in some cases resistance toward additional hormones. Patients affected by this disorder all share a loss-of-methylation (LOM) at the differentially methylated GNAS exon A/B, which reduces expression of the stimulatory G protein α-subunit (Gsα) from the maternal allele. This leads in the proximal renal tubules, where the paternal GNAS allele does not contribute much to expression of this signaling protein, to little or no Gsα expression thereby causing PTH resistance. We now describe a PHP1B patient with a de novo genomic GNAS duplication of approximately 88 kb, which is associated with LOM restricted to exon A/B alone. Multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and whole-genome sequencing (WGS) established that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a small region between two imperfect repeats just upstream of LOC105372695 (centromeric breakpoint). Our novel duplication is considerably shorter than previously described duplications/triplications in that portion of chromosome 20q13 and it does not affect methylation at exons AS and XL. Based on these and previous findings, it appears plausible that the identified genomic abnormality disrupts in cis the actions of a transcript that is required for establishing or maintaining exon A/B methylation. Our findings extend the molecular causes of PHP1B and provide additional insights into structural GNAS features that are required for maintaining maternal Gsα expression and for preventing PTH-resistance. © 2020 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , Cromograninas/genética , Hibridização Genômica Comparativa , Metilação de DNA/genética , Éxons/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Pseudo-Hipoparatireoidismo/genética
13.
Endocrine ; 72(3): 611-618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33179219

RESUMO

Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term "inactivating PTH/PTHrP signaling disorders (iPPSD)" was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.


Assuntos
Disostoses , Pseudo-Hipoparatireoidismo , Doenças Ósseas Metabólicas , Disostoses/diagnóstico , Disostoses/genética , Humanos , Deficiência Intelectual , Ossificação Heterotópica , Osteocondrodisplasias , Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Dermatopatias Genéticas
14.
Eur J Endocrinol ; 184(2): 311-320, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33270042

RESUMO

Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification. Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized. Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients. Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease. Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.


Assuntos
Proteína Relacionada ao Hormônio Paratireóideo/fisiologia , Hormônio Paratireóideo/fisiologia , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/diagnóstico , Terminologia como Assunto , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Disostoses/classificação , Disostoses/genética , Feminino , França/epidemiologia , Inativação Gênica , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/classificação , Deficiência Intelectual/genética , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Mutação , Ossificação Heterotópica/classificação , Ossificação Heterotópica/genética , Osteocondrodisplasias/classificação , Osteocondrodisplasias/genética , Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Pseudo-Hipoparatireoidismo/epidemiologia , Pseudo-Hipoparatireoidismo/genética , Doenças Raras , Estudos Retrospectivos , Transdução de Sinais/genética , Espanha/epidemiologia , Adulto Jovem
15.
J Endocrinol Invest ; 44(2): 245-253, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32661948

RESUMO

BACKGROUND: Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years. FINDINGS: Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available. PURPOSE OF THE REVIEW: This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.


Assuntos
Doenças dos Gânglios da Base/patologia , Calcinose/patologia , Cálcio/metabolismo , Hipoparatireoidismo/fisiopatologia , Pseudo-Hipoparatireoidismo/fisiopatologia , Animais , Doenças dos Gânglios da Base/epidemiologia , Calcinose/epidemiologia , Humanos
16.
J Bone Miner Res ; 36(4): 696-703, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33247854

RESUMO

Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B), we analyzed kindreds with the frequent 3-kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss-of-methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)-resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow-up (31 of 98 versus 6 of 218). This difference in follow-up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD-PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Pseudo-Hipoparatireoidismo , Sintaxina 16 , Criança , Cromograninas/genética , Metilação de DNA , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Masculino , Mutação/genética , Pseudo-Hipoparatireoidismo/genética , Sintaxina 16/genética
17.
Arch Endocrinol Metab ; 65(1): 112-116, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33320452

RESUMO

Pseudohypoparathyroidism comprehends an assorted group of genetically rare disorders that share end-organ resistance to parathyroid hormone. Genetic and epigenetic modifications on guanine nucleotide-binding protein alpha-stimulating gene locus are the most common underlying mechanisms associated with pseudohypoparathyroidism. Biochemical and molecular analysis stratify pseudohypoparathyroidism into types 1A, 1B, 1C, and 2. We describe an unusual case of sporadic pseudohypoparathyroidism type 1B. A 34-year-old Caucasian woman was admitted to the emergency department, with persistent asthenia, limb paresthesias, and tactile hyposensitivity. Her physical examination, previous personal and family histories were unsuspicious, except for mild, intermittent and self-limited complaints of paresthesia during her two pregnancies, but no detailed workup was done. No typical features of Albright hereditary osteodystrophy were observed. The initial laboratory investigation showed elevated parathyroid hormone level (311.2 pg/mL), hypocalcemia (albumin-corrected serum calcium 4.3 mg/dL), hypocalciuria, hyperphosphatemia, hypophosphaturia, and vitamin D deficiency. Combined calcium, vitamin D, and magnesium supplementation was commenced, with symptomatic and analytical improvement. Albeit resolution of vitamin D deficiency, the patient relapsed with mild and intermittent lower limb paresthesias. Pseudohypoparathyroidism was confirmed by molecular identification of the 3-kb STX16 deletion. The treatment was readjusted, and one year later, symptomatic remission was attained. Clinical and biochemical features, and their respective course, along with lack of distinctive features of Albright hereditary osteodystrophy pointed to pseudohypoparathyroidism type 1B. A careful follow-up is needed to avoid complications and recurrence. Once correction of hypocalcemia and hyperphosphatemia is achieved, with no reported complications and recurrence, a good prognosis is anticipated, comparable to the general population.


Assuntos
Hipocalcemia , Pseudo-Hipoparatireoidismo , Deficiência de Vitamina D , Adulto , Feminino , Humanos , Hipocalcemia/genética , Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética
18.
J Pediatr Endocrinol Metab ; 33(11): 1475-1479, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33027051

RESUMO

Objectives The objective of this paper is to report a peculiar case of a patient with pseudohypoparathyroidism type 1b (PHP1B). Pseudohypoparathyroidism (PHP) refers to a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) concentrations as the result of end-organ unresponsiveness to PTH. Case presentation We present a 14-year-old boy, who was admitted with severe symptomatic hypocalcaemia, absence of dysmorphic features and Albright's hereditary osteodystrophy features. Laboratory investigations revealed markedly low serum calcium, high phosphate, markedly elevated PTH levels and vitamin D insufficiency, while magnesium, albumin, ALP and TSH were normal. The clinical and laboratory findings were consistent with PHP1B. Molecular analysis revealed loss of methylation at the AB DMR of the GNAS locus, confirming the diagnosis. Yet no STX16 deletion was detected. Conclusions It is possible that delSTX16- patients carry a defect in an element that controls the methylation both at the GNAS-A/B DMR and at the GNAS-AS2. This rare case emphasizes the need of individualized molecular analysis in PHP1B patients in order to elucidate the possible molecular defect.


Assuntos
Pseudo-Hipoparatireoidismo/diagnóstico , Adolescente , Fatores Etários , Cromograninas/genética , Metilação de DNA/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Grécia , Humanos , Masculino , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/etiologia , Pseudo-Hipoparatireoidismo/genética , Doenças Raras
19.
Nucleic Acids Res ; 48(20): 11394-11407, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33053156

RESUMO

Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.


Assuntos
Metilação de DNA , Embrião de Mamíferos/metabolismo , Impressão Genômica , Células Germinativas/metabolismo , Oócitos/metabolismo , Proteínas Repressoras/metabolismo , Síndrome de Beckwith-Wiedemann/metabolismo , Estudos de Coortes , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , Análise em Microsséries , Mutação , Linhagem , Pseudo-Hipoparatireoidismo/metabolismo , RNA-Seq , Proteínas Repressoras/genética , Irmãos , Transcriptoma , Proteína 28 com Motivo Tripartido
20.
J Pediatr Endocrinol Metab ; 33(9): 1219-1224, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32866120

RESUMO

Objectives Objectives Pseudohypoparathyroidism type 1A (PHP1A) is caused by maternal inheritance of GNAS mutations. It is characterized by the resistance to several hormones, primarily the parathyroid hormone (PTH), and the features of Albright's hereditary osteodystrophy. Case presentation Here, we present a family comprised two affected brothers with PHP1A and identify a novel mutation (c.277C>T) in the GNAS gene. The siblings developed a slightly different presentation in the same clinical condition. Although both patients presented with PTH resistance, which is the hallmark of PHP, the proband showed the thyroid-stimulating hormone resistance with the progression of heterotopic ossification from skin and subcutaneous tissue into deep connective tissue, while the younger brother with normocalcemia did not show the resistance to other hormones. The patients may inherit the mutation from their mother who presumably carries the mutation as a mosaicism. Conclusions Our case highlights the significance of considering mosaicism as an explanation for apparent de novo cases of pseudohypoparathyroidism.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Herança Materna/genética , Mosaicismo , Mutação , Pseudo-Hipoparatireoidismo/etiologia , Irmãos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Prognóstico , Pseudo-Hipoparatireoidismo/patologia
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