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European Journal of Endocrinology Jul 2023Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder... (Observational Study)
Observational Study
BACKGROUND
Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height.
OBJECTIVE
Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls.
METHODS
We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models.
RESULTS
Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy.
CONCLUSION
Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.
Topics: Humans; Adult; Growth Hormone; Retrospective Studies; Human Growth Hormone; Pseudohypoparathyroidism; Dwarfism, Pituitary; Hypopituitarism; Mutation; Body Height; Recombinant Proteins; Growth Disorders; Chromogranins; GTP-Binding Protein alpha Subunits, Gs
PubMed: 37440712
DOI: 10.1093/ejendo/lvad085 -
Journal of Assisted Reproduction and... May 2017Genomic imprinting is a complex epigenetic process that contributes substantially to embryogenesis, reproduction, and gametogenesis. Only small fraction of genes within... (Review)
Review
Genomic imprinting is a complex epigenetic process that contributes substantially to embryogenesis, reproduction, and gametogenesis. Only small fraction of genes within the whole genome undergoes imprinting. Imprinted genes are expressed in a monoallelic parent-of-origin-specific manner, which means that only one of the two inherited alleles is expressed either from the paternal or maternal side. Imprinted genes are typically arranged in clusters controlled by differentially methylated regions or imprinting control regions. Any defect or relaxation in imprinting process can cause loss of imprinting in the key imprinted loci. Loss of imprinting in most cases has a harmful effect on fetal development and can result in neurological, developmental, and metabolic disorders. Since DNA methylation and histone modifications play a key role in the process of imprinting. This review focuses on the role of DNA methylation in imprinting process and describes DNA methylation aberrations in different imprinting disorders.
Topics: Alleles; DNA Methylation; Epigenesis, Genetic; Female; Genomic Imprinting; Histone Code; Humans; Male; Prader-Willi Syndrome
PubMed: 28281142
DOI: 10.1007/s10815-017-0895-5 -
BMC Endocrine Disorders Apr 2022Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the... (Review)
Review
BACKGROUND
Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members.
CASE PRESENTATION AND GENE ANALYSIS
A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient.
CONCLUSIONS
Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.
Topics: Adult; Chromogranins; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Hypocalcemia; Hypokalemia; Pseudohypoparathyroidism; Tetany
PubMed: 35410271
DOI: 10.1186/s12902-022-01011-9 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2022Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to...
Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to parathyroid. The clinical characteristics and genetic features in 4 patients with Type Ib PHP in the Third Xiangya Hospital, Central South University, have been reviewed. All 4 patients had low calcium, high phosphorus, and parathyroid resistance. Among them, 2 patients had slightly elevated thyroid stimulating hormone and mild features of Albright's hereditary osteodystrophy, and one patient had hypokalemia. No guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 () and gene variant associated with hypokalemia were identified using the whole exome sequencing. The results of the methylation-specific multiple ligation-dependent probe amplification showed that there were abnormal methylation of the upstream differentially methylated regions of in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.
Topics: Humans; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Hypokalemia; Calcium; Pseudohypoparathyroidism; Phosphorus
PubMed: 36411698
DOI: 10.11817/j.issn.1672-7347.2022.220029 -
AACE Clinical Case Reports 2020Acrodysostosis is a rare skeletal dysplasia with one gene mutation associated with pseudohypoparathyroidism. We describe a 15-year-old male patient with genetic...
OBJECTIVE
Acrodysostosis is a rare skeletal dysplasia with one gene mutation associated with pseudohypoparathyroidism. We describe a 15-year-old male patient with genetic acrodysostosis who presented with hyperparathyroidism.
METHODS
Laboratory testing, including genetic testing for acrodysostosis and biochemical evaluation for hypercalcemia, were obtained. For evaluation of the source of hyperparathyroidism, parathyroid imaging including technetium (99mTc) sestamibi (MIBI) scan, ultrasound, and 4-dimensional computed tomography scans were performed.
RESULTS
The initial calcium level of 11.7 mg/dL (reference range is 8.4 to 10.2 mg/dL), phosphorus of 2.6 mg/dL (reference range is 2.9 to 5.0 mg/dL), and parathyroid hormone (PTH) of 177 pg/mL (reference range is 15 to 65 pg/mL) were suspicious for hyperparathyroidism. Magnesium, albumin, creatinine, and PTH-related peptide levels were normal. His calcium/creatinine ratio was 0.15, calcium/creatinine clearance ratio was 0.008, and the fractional excretion of phosphorus was 34%. Our patient had no symptoms other than long-standing bone pain. Thyroid ultrasound then MIBI scan did not show a parathyroid adenoma or parathyroid gland hyperplasia. Familial hypocalciuric hypercalcemic syndrome was entertained, but without a family history and documented normal calcium levels throughout childhood, it was considered unlikely. On subsequent testing, his calcium and PTH levels increased. Subsequent imaging including repeat thyroid ultrasound, MIBI scan, and computed tomography did not find a definitive cause. Multiple endocrine neoplasia type 1 genetic testing was negative. Without an adenoma seen to remove surgically, we performed a trial of cinacalcet with successful reduction in PTH and normalization of his calcium and phosphorus levels.
CONCLUSION
Pseudohypoparathyroidism and hypocalcemia are well reported in acrodysostosis. To the best of our knowledge, this is the first reported case of hypercalcemia caused by hyperparathyroidism in a patient with acrodysostosis.
PubMed: 33244495
DOI: 10.4158/ACCR-2020-0103 -
Endocrinology, Diabetes & Metabolism... Jan 2019Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the...
Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.
PubMed: 30703064
DOI: 10.1530/EDM-18-0125 -
BMC Medical Genomics Nov 2021Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic...
BACKGROUND
Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response.
METHODS
Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature.
RESULTS
Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [- 5.05 standard deviation (SD)] to 100.4 cm (- 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (- 2.69 SD) to 145.0 cm (- 2.36 SD), and her increased height SDS was 0.33.
CONCLUSIONS
Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.
Topics: Body Height; Bone and Bones; Child; Child, Preschool; Dwarfism; Female; Growth Hormone; Humans; Limb Deformities, Congenital; Lordosis; Male; Phenotype; Pseudohypoparathyroidism; Receptor, Fibroblast Growth Factor, Type 3; Exome Sequencing
PubMed: 34740356
DOI: 10.1186/s12920-021-01113-8 -
The Journal of Clinical Endocrinology... Oct 2023Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical...
BACKGROUND
Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical features including obesity, neurocognitive impairment, brachydactyly, short stature, parathyroid hormone (PTH) resistance, and resistance to other hormones such as thyroid-stimulating hormone (TSH) have been well described, yet they refer mainly to the full development of the disease during late childhood and adulthood.
OBJECTIVE
A significant delay in diagnosis has been reported; therefore, our objective is to increase awareness on neonatal and early infancy presentation of the diseases. To do so, we analyzed a large cohort of iPPSD/PHP patients.
METHODS
We included 136 patients diagnosed with iPPSD/PHP. We retrospectively collected data on birth and investigated the rate of neonatal complications occurring in each iPPSD/PHP category within the first month of life.
RESULTS
Overall 36% of patients presented at least one neonatal complication, far more than the general population; when considering only the patients with iPPSD2/PHP1A, it reached 47% of the patients. Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, ie, 10.5% and 18.4%, respectively. The presence of neonatal features was associated with earlier resistance to TSH (P < 0.001) and with the development of neurocognitive impairment (P = 0.02) or constipation (P = 0.04) later in life.
CONCLUSION
Our findings suggest that iPPSD/PHP and especially iPPSD2/PHP1A newborns require specific care at birth because of an increased risk of neonatal complications. These complications may predict a more severe course of the disease; however, they are unspecific which likely explains the diagnostic delay.
Topics: Humans; Infant; Infant, Newborn; Chromogranins; Delayed Diagnosis; GTP-Binding Protein alpha Subunits, Gs; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Rare Diseases; Retrospective Studies; Thyrotropin
PubMed: 37098127
DOI: 10.1210/clinem/dgad236 -
Journal of Bone and Mineral Research :... Mar 2022Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved...
Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Brachydactyly; DNA-Binding Proteins; Fingers; Hair Diseases; Humans; Langer-Giedion Syndrome; Nose; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Repressor Proteins
PubMed: 34897794
DOI: 10.1002/jbmr.4490 -
The Journal of Pediatrics Nov 2023We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. (Observational Study)
Observational Study
OBJECTIVE
We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening.
STUDY DESIGN
This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated.
RESULTS
We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity.
CONCLUSIONS
Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.
Topics: Humans; Child; Body Mass Index; Age of Onset; Obesity; Genetic Testing; Heterozygote; Receptor, Melanocortin, Type 4
PubMed: 37473986
DOI: 10.1016/j.jpeds.2023.113619