Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a <i><scp>GNAS</scp></i> mutation

Leclercq, Valérie; Benoît, Valérie; Lederer, Damien; Delaunoy, Mélanie; Ruiz, Marcela; Halleux, Claire de; Robaux, Olivier; Wanty, Catherine; Maystadt, Isabelle

doi:10.1002/ccr3.1739

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…Albright’s Hereditary Osteodystrophy (OMIM#103580) is caused by a mutation in GNAS1 , leading to a defect in the alpha subunit of G proteins (Gαs) coupled to transmembrane receptors. Gαs deficiency in imprinted regions of the hypothalamus results in early onset excess weight gain, round facies, brachydactyly, metacarpia of the hands and/or feet, and heterotopic ossifications, as well as t hormonal alterations [ 50 ]. The link to the HPO website for Albright’s Hereditary Osteodystrophy is https://hpo.jax.org/app/browse/disease/OMIM:103580 .…”

Section: Identification and Diagnosis Of Classical Obesity Syndromesmentioning

confidence: 99%

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

Rodríguez‐López

Gimeno-Ferrer

Santos

et al. 2022

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Background: Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Objective: Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. Methods: The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient’s family is also of importance. Results: The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. Conclusion: With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.

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Section: Identification and Diagnosis Of Classical Obesity Syndromesmentioning

confidence: 99%

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

Rodríguez‐López

Gimeno-Ferrer

Santos

et al. 2022

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“…Loss of GNAS is characterized by progressive heterotopic ossification (HO) in extraskeletal soft tissue (Cong et al 2021). Although only a few clinical craniosynostosis cases due to loss of GNAS have been reported, infantile lethal cerebral infarction after surgery was documented (Leclercq et al 2018). In mice, it is assumed that skull deformity due to the loss of Gnas results from altered or accelerated mesenchymal progenitor/stem cell specification or commitment (Xu, Khan, et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Gnas Loss Causes Chondrocyte Fate Conversion in Cranial Suture Formation

Liu

Zhou

et al. 2022

J Dent Res

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Calvaria development is distinct from limb formation. Craniosynostosis is a skull deformity characterized by premature cranial suture fusion due to the loss of the GNAS gene and, consequently, its encoded protein Gαs. This birth defect requires surgery, with potential lethal consequences. So far, hardly any early-stage nonsurgical interventions for GNAS loss-related craniosynostosis are available. Here, we investigated the role of the Gnas gene in mice in guarding the distinctiveness of intramembranous ossification and how loss of Gnas triggered endochondral-like ossification within the cranial sutures. Single-cell RNA sequencing (scRNA-seq) of normal neonatal mice cranial suture chondrocytes showed a Hedgehog (Hh) inactivation pattern, which was associated with Gαs signaling activation. Loss of Gnas evoked chondrocyte-to-osteoblast fate conversion and resulted in cartilage heterotopic ossification (HO) within cranial sutures and fontanels of the mouse model, leading to a skull deformity resembling craniosynostosis in patients with loss of GNAS. Activation of ectopic Hh signaling within cranial chondrocytes stimulated the conversion of cell identity through a hypertrophy-like stage, which shared features of endochondral ossification in vivo. Reduction of Gli transcription activity by crossing with a loss-of-function Gli2 allele or injecting GLI1/2 antagonist hindered the progression of cartilage HO in neonatal stage mice. Our study uncovered the role of Gαs in maintaining cranial chondrocyte identity during neonatal calvaria development in mice and how reduction of Hh signaling could be a nonsurgical intervention to reduce skull deformity in craniosynostosis due to loss of GNAS.

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“…PHP1 is further differentiated according to the presence (PHP1A, MIM #103580, and PHP1C, MIM #612462) or absence (PHP1B, MIM #603233) of Albright hereditary osteodystrophy (AHO) ( 3 ). AHO is a clinical entity encompassing heterogeneous clinical findings such as brachydactyly, rounded face, short stature, subcutaneous ossification and variable degrees of intellectual deficiency ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance

et al. 2022

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PTH resistance is characterized by elevated parathyroid hormone (PTH) levels, hypocalcemia, hyperphosphatemia and it is classically associated with GNAS locus genetic or epigenetic defects. Inactivating PTH/PTHrP signaling disorders (iPPSD) define overlapping phenotypes based on their molecular etiology. iPPSD1 is associated with PTH1R variants and variable phenotypes including ossification anomalies and primary failure of tooth eruption but no endocrine disorder. Here we report on a 10-month-old child born from consanguineous parents, who presented with mild neurodevelopmental delay, seizures, enlarged fontanelles, round face, and bilateral clinodactyly. Hand x-rays showed diffuse delayed bone age, osteopenia, short metacarpal bones and cone-shaped distal phalanges. A diagnosis of PTH resistance was made on the basis of severe hypocalcemia, hyperphosphatemia, elevated PTH and normal vitamin D levels on blood sample. The patient was treated with calcium carbonate and alfacalcidol leading to rapid bio-clinical improvement. Follow-up revealed multiple agenesis of primary teeth and delayed teeth eruption, as well as Arnold-Chiari type 1 malformation requiring a ventriculoperitoneal shunt placement. GNAS gene analysis showed no pathogenic variation, but a likely pathogenic homozygous substitution c.723C>G p.(Asp241Glu) in PTH1R gene was found by trio-based whole exome sequencing. We studied the deleterious impact of the variant on the protein conformation with bioinformatics tools. In conclusion, our study reports for the first time PTH resistance in a child with a biallelic PTH1R mutation, extending thereby the clinical spectrum of iPPSD1 phenotypes.

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Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a GNAS mutation

Cited by 4 publications

References 24 publications

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

Gnas Loss Causes Chondrocyte Fate Conversion in Cranial Suture Formation

Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance

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