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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 -
European Journal of Endocrinology Nov 2023Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding...
BACKGROUND
Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO).
OBJECTIVES
To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them.
METHODS
Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them.
RESULTS
A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants.
CONCLUSIONS
This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.
Topics: Humans; Child, Preschool; Prospective Studies; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies
PubMed: 37837607
DOI: 10.1093/ejendo/lvad142 -
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 -
Orphanet Journal of Rare Diseases Nov 2023Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH...
BACKGROUND
Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH resistant have been widely studied, glucolipid metabolism abnormalities observed in PHP1 patients have received little attention. The aim of this research is to explore the glucolipid metabolism features in a rather large cohort of PHP1 patient. In the current study, PHP1 patients and primary hyperparathyroidism patients as well as normal control were recruited for the investigation. Glucolipid metabolic indices as well as the level of four adipokines were examined.
RESULTS
A total of 49 PHP1 patients, 64 PHPT patients and 30 healthy volunteers were enrolled. A trend of higher HOMA-β index was found in PHP1 patients than normal controls (median 97.08% vs 68.19%, p = 0.060). Both the PHP1 and PHPT group presented with significantly lower TNFα level compared to normal controls (average 10.74 pg/ml and 12.53 pg/ml vs 15.47 pg/ml, p = 0.002 and 0.041, respectively). FGF21 level was significantly higher in PHPT group than in PHP1 group (median 255.74 pg/ml vs 167.46 pg/ml, p = 0.019). No significant difference in glucolipid metabolic indices and adipokines was found between PHP1A or PHP1B patients and normal controls, while overweight/obese PHP1 patients tended to have higher leptin than normal-BMI cases (p = 0.055). Multiple linear regression analysis showed BMI rather than PTH or HOMA-IR to be an independent variable of leptin in PHP1.
CONCLUSION
Metabolic stress given upon especially overweight PHP1 patients may resulted in possible β-cell compensation. Elevated TNFα may be related with hyper-PTH level regardless of calcium level.
Topics: Humans; Calcium; Leptin; Adipokines; Tumor Necrosis Factor-alpha; Overweight; Pseudohypoparathyroidism
PubMed: 38017461
DOI: 10.1186/s13023-023-02979-w -
Diabetes, Metabolic Syndrome and... 2024Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we...
Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we report a case of a patient with pseudohypoparathyroidism type IB (PHPIB) and subclinical hypothyroidism, analyze the clinical and genetic data of his family members, review the relevant literature, and classify and discuss the pathogenesis and clinical characteristics of each subtype. Finally, we discuss the treatment approach to improve clinicians' understanding of the disease.
PubMed: 38765469
DOI: 10.2147/DMSO.S458405 -
Mutation Research. Reviews in Mutation... 2024GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This... (Review)
Review
BACKGROUND
GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that Gα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β- and β-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.
SCOPE OF REVIEW
This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying Gα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.
MAJOR CONCLUSIONS
Gα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Epigenesis, Genetic; Obesity; Animals; Pseudohypoparathyroidism; Mutation; Receptor, Melanocortin, Type 4; Age of Onset
PubMed: 38103632
DOI: 10.1016/j.mrrev.2023.108487 -
Frontiers in Cell and Developmental... 2023Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer...
Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the :TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders.
PubMed: 37635873
DOI: 10.3389/fcell.2023.1237629 -
Cureus Feb 2024Albright's hereditary osteodystrophy is a rare hereditary disease due to a mutation of the complex guanine nucleotide-binding protein, alpha-stimulating activity...
Albright's hereditary osteodystrophy is a rare hereditary disease due to a mutation of the complex guanine nucleotide-binding protein, alpha-stimulating activity polypeptide. This condition is commonly associated with type 1A and 1C pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism due to resistance of parathyroid hormone. Patients present with specific characteristics such as brachydactyly, short stature, round facies, subcutaneous ossifications, developmental delay, and obesity, associated with hypocalcemia and hyperphosphatemia. This case presents a 55-year-old woman with short stature and neurocognitive impairment, who was admitted to the emergency department with acute decompensated heart and respiratory failure. On admission, hypocalcemia and hyperphosphatemia were noted, which in combination with the patient's clinical history led to an etiological investigation. This case stresses the importance of not only treating the acute disease but also looking at the patient and their clinical and analytical features to diagnose this disease and prevent its complications.
PubMed: 38558694
DOI: 10.7759/cureus.55200 -
JCEM Case Reports Jul 2023PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is...
PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is subdivided into different types according to its different pathogenesis and phenotype. PTH receptor is the alpha subunit of stimulatory G protein (Gα)-coupled receptor. Pathogenic variants of GNAS gene, encoding for Gα, lead to reduced Gα function and PTH resistance. We report a patient with PHP type 1a, with no documented evidence of hypocalcemia, presenting with AHO phenotype and multihormone resistance to PTH, TSH, and GnRH. Her genetic testing showed a novel heterozygous pathogenic variants, a c.934T > G change in exon 11 in adenylate cyclase stimulatory G protein that has not been reported in the literature so far.
PubMed: 37908988
DOI: 10.1210/jcemcr/luad088 -
Medicina Clinica Dec 2023The clinical and biochemical overlap of various pathologies of phosphocalcic metabolism can lead to misdiagnosis and consequent clinical management. One example is...
BACKGROUND AND OBJECTIVE
The clinical and biochemical overlap of various pathologies of phosphocalcic metabolism can lead to misdiagnosis and consequent clinical management. One example is pseudohypoparathyroidism, which can be confused with vitamin D-dependent rickets (VDDR1) if appropriate biochemical determinations are not performed.
PATIENTS AND METHODS
Two pairs of siblings, from independent families, were clinically diagnosed in adolescence with pseudohypoparathyroidism due to hypocalcaemia, elevated parathyroid hormone levels and normal or elevated phosphorus values. After ruling out alterations in GNAS, a massive sequencing study of genes associated with other differential diagnoses was carried out.
RESULTS
Two genetic variants in the CYP27B1 gene potentially associated with the phenotype were identified. Pathogenic variants in this gene are associated with VDDR1A. Clinical-biochemical re-evaluation of the patients confirmed this diagnosis and treatment was adapted.
CONCLUSIONS
Although VDDR1A is an infrequently diagnosed pathology in adulthood, in cases of hypocalcaemia with elevated PTH values, determination of the 1,25(OH)D and 25(OH)D forms of vitamin D is relevant to reach a correct diagnosis.
Topics: Adolescent; Humans; Hypocalcemia; Parathyroid Hormone; Vitamin D Deficiency; Pseudohypoparathyroidism; Vitamin D
PubMed: 37500374
DOI: 10.1016/j.medcli.2023.06.009