Nonclassic features of pseudohypoparathyroidism type 1A

Jüppner, Harald

doi:10.1097/med.0000000000000306

Cited by 27 publications

(23 citation statements)

References 67 publications

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“…With both disorders, there is a high prevalence of recurrent otitis media requiring typanostomy tubes, an increased rate of hearing loss, and a high risk of sleep apnea. [7, 19, 21] These clinical features were evident in our PHP1A sample and may indicate craniofacial abnormalities in children with PHP1A similar to those documented in Down syndrome. [21] These possible anatomical abnormalities, combined with generalized hypotonia, may lead to the increased rates of sleep apnea seen in individuals with PHP1A, though further research regarding the hypotonic and craniofacial phenotype in this population is needed.…”

Section: Discussionsupporting

confidence: 53%

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Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism

et al. 2018

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Background/Aims: Pseudohypoparathyroidism (PHP) is a rare, genetic disorder. Patients with PHP may have increased prevalence of obstructive sleep apnea (OSA) but this has not been prospectively studied. Methods: We enrolled children aged 6–18 years with PHP and matched controls. Evaluation included physical examination, medical history, and polysomnography. Results: Fifteen children with PHP type 1A (PHP1A) and 15 controls completed the study. Both groups were obese (BMI 32.2 ± 8.7 vs. 31.7± 6.5). The majority of PHP1A patients required tympanostomy tubes (86.7%) and adenotonsillectomy (73.3%). The primary outcome, i.e., the obstructive disturbance index, was significantly higher in PHP1A children versus controls (1.8 ± 2.3 vs. 0.6 ± 0.5, p = 0.045). Children with PHP1A were more likely to have OSA compared with controls (60.0 vs. 13.3%, p = 0.008). Three siblings with PHP type 1B (PHP1B) were also studied (BMI 25.9 ± 9.0). None had a history of adenotonsillectomy, one had tympanostomy tubes. The obstructive disturbance index (2.0 ± 2.3) was similar to that of children with PHP1A. Two (66.7%) PHP1B participants had OSA. Conclusion: Children with PHP1A are at an increased risk for OSA compared with similarly obese peers. They also have higher rates of otitis media and adenotonsillar hypertrophy. Screening for OSA should be considered in all patients with PHP1A and possibly PHP1B though more research is needed.

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Section: Discussionsupporting

confidence: 53%

“…[7, 18, 19] In adults, asthma has been associated with the development of OSA. [20] In this study, asthma was more prevalent in the PHP1A group than in the control group and may account for the increased risk of OSA in this population.…”

Section: Discussionmentioning

confidence: 99%

Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism

et al. 2018

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“…Furthermore, TSH is frequently elevated; particularly PHP1A patients present with additional abnormalities, such as early‐onset obesity, short stature, and various degrees of neurodevelopmental challenges, findings that are referred to as Albright hereditary osteodystrophy (AHO). The same or similar mutations on the paternal allele lead to PPHP, ie, AHO without hormonal resistance and without obesity or neurocognitive abnormalities …”

Section: Discussionmentioning

confidence: 99%

“…The same or similar mutations on the paternal allele lead to PPHP, ie, AHO without hormonal resistance and without obesity or neurocognitive abnormalities. (2)(3)(4)(5)10,11,(35)(36)(37) Likewise, PTHrP haploinsufficiency can lead to variable shortening of one or multiple metacarpals and metatarsals, but also to short stature implying that chondrocytes in multiple growth plates undergo accelerated differentiation. (25)(26)(27)(28)(29)(30)(31) It is therefore likely that haploinsufficiency of PTHrP-dependent signaling at the PTHR1 reduces intracellular cAMP levels in growth plate chondrocytes to a similar extent as heterozygous PDE4D, PDE3A, and PRKAR1A mutations, or the reduction of Gsa protein levels through genetic or epigenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A Heterozygous Splice-Site Mutation in PTHLH Causes Autosomal Dominant Shortening of Metacarpals and Metatarsals

Reyes

Bravenboer

Jüppner

2018

Journal of Bone and Mineral Research

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Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type la (PHP1A) or pseudo-PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsα). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III-1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A>G change at nucleotide —3 upstream of PTHLH exon 3 that encodes the last two amino acids of the prosequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II-2,190/II-1), and her affected twin sons (190/IV-1, 190/IV-2), but not in her unaffected daughter (190/IV-3) and sister (190/III-2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV-2 (affected) and 190/IV-3 (unaffected) was PCR-amplified using forward primers located either in PTHLH exon 1 (noncoding) or exon 2 (presequence and most of the prosequence), and reverse primers located in the 3’-noncoding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for the affected son 190/IV-2, but not for the unaffected daughter 190/IV-3, a heterozygous insertion of genomic nucleotides —2 and —1 causing a frameshift after residue 34 of the pre/prosequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations.

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“…Several mechanisms can be responsible for the excessive weight gain. In patients with PHP1A, reduced energy expenditure caused by the decreased Gsα-mediated signaling in brown or beige fat cells, as well as impaired signaling at the melanocortin 4 receptor leading to hyperphagia and thus increased caloric intake have been proposed as important mechanisms leading to obesity (6)(7)(8). Furthermore, the resistance to TSH and growth hormonereleasing-hormone may play a role in the development of obesity (2).…”

Section: Introductionmentioning

confidence: 99%

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

et al. 2020

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Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1-13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMPsignaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight. Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years. Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS. Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA. Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.

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Nonclassic features of pseudohypoparathyroidism type 1A

Cited by 27 publications

References 67 publications

Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism

Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism

A Heterozygous Splice-Site Mutation in PTHLH Causes Autosomal Dominant Shortening of Metacarpals and Metatarsals

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

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