Table 3.

Disorders of GNAS Inactivation: Risk to Sibs of a Proband Based on the Parents' Genetic Status

ParentDisorder in ProbandClinical Status of ParentEvaluation of ParentGenetic Status of ParentRisk to Sibs of Proband
FatherPHP-IaNot affectedUsually no further eval/testingFather will not be heterozygous for mechanism of GNAS inactivation identified in proband.Depends on genetic status of mother
PPHPMay be unaffected or have PHP-Ia, PHP-Ic, PPHP, OC, or POH 1, 2, 3Test for proband’s GNAS pathogenic variant
Detailed physical examination & measurement of serum concentration of PTH, calcium, phosphorous
If proband’s GNAS pathogenic variant not detected in paternal leukocyte DNA, explanations include: If father affected: 50% for PPHP or POH/OC
If father clinically unaffected: presumed low
If GNAS pathogenic variant not found in paternal leukocyte DNA: slightly > general population (i.e., theoretic possibility of germline mosaicism)
MotherPHP-IaMay be unaffected or have PHP-Ic, PPHP, POH, or OC 1, 2, 4Test for genetic mechanism of GNAS inactivation identified in proband
Detailed physical exam & measurement of serum concentration of PTH, calcium, phosphorous
If mechanism of GNAS inactivation in proband not detected in maternal leukocyte DNA, possible explanations: If mother affected: 50% for PHP-Ia, PHP-Ib, or PHP-Ic
If mother clinically unaffected: presumed low
If GNAS inactivation alternation not identified in maternal leukocyte DNA: slightly > general population (i.e., possibility of germline mosaicism5
PPHPNot affectedNo further eval/testingNot heterozygous for proband's GNAS pathogenic variantDepends on father's genetic status
POHTypically not affected 6If father's eval normal, mol gen testing and/or clinical eval of mother may be appropriate.Typically not heterozygous for proband's GNAS pathogenic variantUnknown

OC = osteoma cutis; PHP-Ia = pseudohypoparathyroidism Ia; PHP-Ib = pseudohypoparathyroidism Ib; PHP-Ic = pseudohypoparathyroidism Ic; POH = progressive osseous heteroplasia; PPHP = pseudopseudohypoparathyroidism; PTH = parathyroid hormone


Although some probands diagnosed with a disorder of GNAS inactivation have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in other family members.


If the parent is the individual in the family in whom the genetic alteration first occurred, the parent may have somatic mosaicism and may be mildly/minimally affected.


The endocrine features of PHP-1a may in some cases become apparent after the development of findings of AHO, suggesting that an individual may be incorrectly diagnosed initially as PPHP if an AHO phenotype occurs prior to the onset of endocrine abnormalities. In this case, maternal testing may identify a genetic or epigenetic cause.


Elli et al [2014b] reported an individual with PHP-1b who inherited an STX16 or other regulatory imprinting element deletion from his asymptomatic mother whose deletion was on her paternally inherited allele.


POH/OC is more often inherited from the father; however, features of POH/OC are on occasion due to maternal inheritance.

From: Disorders of GNAS Inactivation

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