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The Journal of Clinical Endocrinology... Jan 2024Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy....
CONTEXT
Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis.
OBJECTIVE
The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes.
METHODS
A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted.
RESULTS
Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean -2.5 SD) and 5 females had primary or secondary amenorrhea.
CONCLUSION
Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation.
Topics: Infant, Newborn; Child; Adult; Humans; Female; Child, Preschool; GTP-Binding Protein alpha Subunits, Gs; Follow-Up Studies; Congenital Hypothyroidism; Retrospective Studies; Chromogranins; Pseudohypoparathyroidism; Obesity
PubMed: 37669316
DOI: 10.1210/clinem/dgad524 -
Child Neurology Open 2023Genetic evaluation of a teenager with seizure found no pathogenic variant in a large gene panel, but an incidental likely pathogenic variant, deemed to cause MODY1...
Genetic evaluation of a teenager with seizure found no pathogenic variant in a large gene panel, but an incidental likely pathogenic variant, deemed to cause MODY1 diabetes. Diabetes history was absent and glycated hemoglobin normal, but serum calcium was severely low, with abnormally high parathyroid hormone. Thus, pseudohypoparathyroidism was suspected and confirmed by molecular genetic testing. Calcium and calcitriol supplementation led to calcium normalization and neurological symptom improvement. Given the absence of personal or family diabetes history, the variant was reassessed and found to encode an alternative transcript with poor expression and activity levels, hence downgraded on expert advice from 'likely pathogenic' to 'likely benign'. Besides illustrating the importance of structured medical workup before launching extensive targeted exome sequencing, this case highlights the need for caution in incidental finding interpretation in patients lacking compatible phenotype or family history, and the value of expert advice in such variant interpretation.
PubMed: 37664540
DOI: 10.1177/2329048X231199327 -
Osteoporosis International : a Journal... Jan 2024Bone lytic lesions are a possible complication of pseudohypoparathyroidism type 1B, in undertreated adult patients. Whole body [18F] F-fluorocholine PET/CT is a useful...
Bone lytic lesions are a possible complication of pseudohypoparathyroidism type 1B, in undertreated adult patients. Whole body [18F] F-fluorocholine PET/CT is a useful imaging tool to assess brown tumor progression in this context. We describe the case of a 33-year-old woman, referred for the diagnostic evaluation of lytic bone lesions of the lower limbs, in the context of asymptomatic pseudohypoparathyroidism. She had been treated with alfacalcidol and calcium during her childhood. Treatment was discontinued at the age of 18 years old because of the lack of symptoms. A femur biopsy revealed a lesion rich in giant cells, without malignancy, consistent with a brown tumor. Laboratory tests showed a parathyroid level at 1387 pg/ml (14-50). Whole-body Fluorocholine PET/CT revealed hypermetabolism of bone lesions. The final diagnosis was brown tumors related to hyperparathyroidism complicating an untreated pseudohypoparathyroidism. Genetic testing confirmed PHP type 1B. Pseudohypoparathyroidism with radiographic evidence of hyperparathyroid bone disease, is a very rare condition due to parathyroid hormone resistance in target organs, i.e., kidney resistance, but with conserved bone cell sensitivity. It has been reported in only a few cases of pseudohypoparathyroidism type Ib. Long-term vitamin D treatment was required to correct bone hyperparathyroidism. With this rationale, the patient was treated with calcium, alfacalcidol, and cholecalciferol. One-year follow-up showed complete resolution of pain, improvement in serum calcium, and regression of bone lesions on [18F]F-fluorocholine PET/CT. This case illustrates the usefulness of [18F]F-fluorocholine PET/CT for the imaging of brown tumors in pseudohypoparathyroidism type 1B, and emphasizes the importance of calcium and vitamin D treatment in adult patients, to avoid the deleterious effects of high parathyroid hormone on skeletal integrity.
Topics: Humans; Adult; Female; Child; Adolescent; Calcium; Positron Emission Tomography Computed Tomography; Osteitis Fibrosa Cystica; Pseudohypoparathyroidism; Parathyroid Hormone; Hyperparathyroidism; Vitamins; Vitamin D; Bone Diseases; Neoplasms; Choline
PubMed: 37644196
DOI: 10.1007/s00198-023-06878-5 -
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 -
Indian Journal of Pediatrics Jan 2024
Topics: Humans; Pseudohypoparathyroidism; Genomic Imprinting; Mutation; DNA Methylation; GTP-Binding Protein alpha Subunits, Gs; Chromogranins
PubMed: 37548842
DOI: 10.1007/s12098-023-04787-3 -
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 -
Anales de Pediatria Aug 2023Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the...
Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the presence of hyperphosphatemia and hypocalcaemia of varying severity. Early-onset obesity is a feature of PHP type 1A. This article discusses the need to establish uniform criteria to guide the nutritional management of patients with PHP. A decrease in energy expenditure calls for an adjustment of the energy content of the diet. Reducing the intake of foods rich in inorganic phosphorus helps to manage hyperphosphataemia. Targeted nutrition should be part of the treatment plan of children and adolescents with PHP, since it contributes to modulating the calcium and phosphorus metabolism imbalances characteristic of these patients.
Topics: Adolescent; Child; Humans; Pseudohypoparathyroidism; Parathyroid Hormone; Nutritional Status; Phosphorus
PubMed: 37481364
DOI: 10.1016/j.anpede.2023.05.007 -
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