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What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis
- Source :
- BMC Medical Genetics, BMC Medical Genetics, Vol 19, Iss 1, Pp 1-10 (2018), Addi. Archivo Digital para la Docencia y la Investigación, instname
- Publication Year :
- 2017
-
Abstract
- Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes. The study was supported by funding from a research project grant (PI13/00467) from the Instituto de Salud Carlos III (Carlos III Institute of Health) of the Ministry of Economy and Competitiveness (Spain), co-financed by the European Regional Development Fund, and the Department of Health of the Basque Government (GV2014111017). AP is partly supported by the University of the Basque Country (Ref: 48198). GPN is partly supported by the I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09).
- Subjects :
- 0301 basic medicine
Male
Candidate gene
Gene Dosage
030105 genetics & heredity
Langer–Giedion syndrome
GTP-Binding Protein alpha Subunits, Gs
Child
identifies pde4d mutations
Albright's hereditary osteodystrophy
growth-hormone deficiency
Genetics (clinical)
langer-giedion-syndrome
Genetics
biology
medicine.diagnostic_test
Brachydactyly
brachydactyly
pseudohypoparathyroidism
autosomal-dominant hypertension
trichorhinophalangeal syndrome
DNA-Binding Proteins
Phenotype
Child, Preschool
Pseudohypoparathyroidism
Female
hormone resistance
Research Article
Adult
lcsh:Internal medicine
lcsh:QH426-470
Adolescent
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
Diagnosis, Differential
03 medical and health sciences
GNAS complex locus
medicine
Chromogranins
severe osteoporosis
Humans
Genetic Testing
Hormone resistance
lcsh:RC31-1245
rhino-phalangeal-syndrome
Genetic testing
business.industry
Parathyroid Hormone-Related Protein
Infant
medicine.disease
Cyclic Nucleotide Phosphodiesterases, Type 4
short stature
Repressor Proteins
lcsh:Genetics
Short stature
brachydactyly type-e
Genetic Loci
albright's hereditary osteodystrophy
mental-retardation
Mutation
biology.protein
Albright’s hereditary osteodystrophy
Differential diagnosis
business
Transcription Factors
Subjects
Details
- ISSN :
- 14712350
- Volume :
- 19
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC medical genetics
- Accession number :
- edsair.doi.dedup.....7542cf0f40f9c8d56abd953920ccac7f