PHP 1A and AHO

Pseudohypoparathyroidism Type 1A (PHP 1a)and Spectrum [includes Albright Hereditary Osteodystrophy (AHO), Pseudopseudohypoparathyroidism (PPHP), and Progressive Osseous Heteroplasia (POH)]
	Gene:	GNAS; chr20pq13.2

Syndrome Information
	Clinical Description:	PHP1a: End organ resistance to parathyroid hormone (PTH), Thyroid Stimulating Hormone (TSH) and gonadotrophins. Laboratory evaluation reveals hypocalcemia, hyperphosphatemia and elevated serum parathyroid hormone (PTH). Patients also have physical findings collectively known as Albright Hereditary Osteodystrophy (AHO). AHO is characterized by short stature, obesity, round face with flat nasal bridge, brachydactyly, subcutaneous ossification and possible / variable developmental delay. PPHP: Patients have the physical findings of Albright Hereditary Osteodystrophy but do not show hormone resistance. POH: Infantile onset ossification of the dermis that progresses to bone formation in deeper tissues. POH is usually not associated with PHP 1a or PPHP, although patients with AHO do have subcutanoeus ossifications. Some PHP1b patients may manifest clinical features that overlap with PHP1a such as bracydactyly or mild features of AHO.
	Inheritance Pattern:	Autosomal dominant or non-inherited epigenetic change**
	Genotype-Phenotype Correlation:	None known; GNAS-related disorders are caused by inactivating mutations; however, this an imprinted locus, and the phenotype is determined by affected allele's parental origin (maternal: PHP1a; paternal: PPHP or POH).

Test Information
	Test Method:	Bidirectional sequencing of the coding regions and intron-exon boundaries of GNAS;automatically reflexed to methylation analysis by bisulfite sequencing of a portion of the Exon 1A Differentially Methylated Region (DMR) of the GNAS locus.
	Clinical Utility:	Identification of causative mutations or epigenetic defects in known or highly suspicious cases of a GNAS-related disease; targeted testing of relatives of proband; predictive prenatal testing when familial sequence-based mutation is known. This assay is NOT designed to detect the somatic gain of function mutations in GNAS that are associated with McCune Albright Syndrome.
	Clinical Sensitivity:	GNAS point mutations are expected in approximately 80% of patients with a clinical diagnosis of PHP1A or PPHP/AHO. This assay can also detect approximately 72% of mutations associated with Progressive Osseous Heteroplasia (POH) Methylation defects of the GNAS locus may be identified in 10-60% of patients with a clinical diagnosis of PHP1a who do not have mutations in Gsa-coding GNAS exons. Up to 2% of samples evaluated by the methylation assay will demonstrate a partial loss of methylation (LOM) in the GNAS exon 1A region (either partial LOM across all CpG sites or partial/complete LOM at some, but not all, CpG sites), and the clinical significance will be uncertain.
	Analytic Sensitivity:	Sequencing: Greater than 97% for nucleotides analyzed. All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction. Methylation: Greater than 99% accuracy for nucleotides evaluated by bisulfite sanger sequencing as compared with bisulfate pyrosequencing. All reports will indicate the number of CpG sites analyzed. Our analysis parameters are designed to detect greater than 10% methylation at the observed CpG sites
	Turn Around Time:	Sequencing: 3 weeks Methylation: 2-3 weeks
	Fee and CPT Codes:	Sequencing: $1478 for routine testing on a blood sample 83891 x 1; 83898 x 14; 83904 x 24; 83909 x 24; 83912 x 1 Methylation: $410 for routine testing on an in-house sample 83898 x 1; 83904 x 2; 83909 x 2; 83912 x 1 Please contact the lab to arrange testing for known mutations on blood or prenatal samples.

Special Considerations
	** There is a continuing question regarding whether patients with methylation defects of the GNAS Exon 1A DMR and some features of mild AHO are more appropriately classified as PHP1b patients (more consistent with mutational mechanism) or PHP1a patients (perhaps more consistent with initial clinical presentation). Thorough clinical and endocrinological evaluations are necessary to confirm a specific diagnosis. The methylation assay examines the GNAS Exon 1A DMR for the loss of methylation pattern associated with some cases of PHP1a, but will not provide evidence regarding the cause of the methylation defect; therefore, a recurrence risk cannot be estimated in methylation positive patients. Prenatal methylation testing is currently not available.

	INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.
Helpful Links
	Sample Requirements Requisition and Billing forms Clinical Information on Pseudohypoparathyroidism type 1a (PHP1a) Pseudopseudohypoparathyroidism (PPHP) Progressive Osseous Heteroplasia (POH) Link to the General Test Information page for a discussion of the uses and limitations of genetic testing Patient and Family Page for general resources on genetic testing.