Disorders of GNAS Inactivation

Clinical characteristics.

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC).

PHP-Ia and PHP-Ic are characterized by:

• End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and
• The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb).

Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly).

PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity.

POH and OC are even more restricted variants of PPHP:

• POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia.
• OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.

Diagnosis/testing.

The diagnosis of a disorder of GNAS inactivation is established in a proband with all or some of the characteristic clinical and endocrine findings and evidence on molecular genetic testing of a genetic or epigenetic alteration resulting in lack of expression/function of the GNAS complex locus.

PHP-Ia,.-Ib, and -Ic are associated with reduced or absent expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) due to one of the following:

• An inactivating GNAS pathogenic variant
• A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus
• Isolated epimutations
• Paternal 20q disomy

PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal GNAS allele due to an inactivating GNAS pathogenic variant; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal GNAS allele) as a result of an inactivating GNAS pathogenic variant.

Management.

Treatment of manifestations: Deficiencies of parathyroid hormone, thyroid hormone, and gonadotropins due to hormone resistance are treated in a standard manner. Growth hormone replacement therapy should be considered if screening for growth hormone deficiency with appropriate provocative testing is abnormal. Subcutaneous ossifications that are superficial and well circumscribed may be surgically removed when they are large or cause local irritation, although they may recur. Obesity tends to be the most difficult manifestation to treat as individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia; thus, the usual recommendation of reduced caloric intake and increased physical activity may be less successful than in persons with obesity from other causes.

Surveillance: Routine monitoring of:

• Endocrine function: measurement of serum concentration of PTH, calcium and phosphate, TSH and free T4, and urinary calcium excretion;
• Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing);
• New and/or enlarging ectopic ossifications;
• Development of and/or progression of cataracts; and
• Psychoeducational needs regarding school assistance / educational support and developmental therapies (e.g., physical, occupational, and speech therapy).

Agents/circumstances to avoid: Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment.

Pregnancy management: For women with a disorder of GNAS inactivation that affects the maternal allele: Monitoring of serum concentration of calcium and thyroid studies (TSH, free T4) throughout pregnancy, labor, and the postpartum period and supplementation of calcium, vitamin D, and thyroid hormone as needed.

Genetic counseling.

Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele. Of individuals with a disorder of GNAS inactivation, approximately 38% have an affected parent and 38% have a de novo GNAS pathogenic variant; in the remaining approximately 25% the cause is unknown.

Each child of an individual with a disorder of GNAS inactivation has a 50% chance of inheriting the parent's genetic alteration (except for simplex cases with PHP-1b for whom the mode of inheritance is not well established). If the maternal GNAS complex locus is affected, her offspring are at risk for PHP-Ia, PHP-Ib (when associated with deletions at the imprinting regulatory elements), or PHP-Ic; if the paternal allele has an inactivating GNAS pathogenic variant, his offspring are at risk for PPHP or POH/OC. If the genetic alteration in the GNAS complex locus or the GNAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are technically possible.

Suggestive Findings

A disorder of GNAS inactivation should be suspected in individuals with the following phenotypes.

Pseudohypoparathyroidism Ia (PHP-Ia) and pseudohypoparathyroidism Ic (PHP-Ic). The most readily recognized form of PHP is PHP-Ia, which has clinical and endocrine features similar to PHP-Ic. Note: PHP-Ic differs from PHP-Ia on the basis of normal functional activity of Gsα (the protein encoded by GNAS) determined in some biochemical assays based on receptor-independent activation of Gsα [Levine 2012].

PHP-Ia and PHP-Ic should be suspected in individuals with some of the following clinical and endocrine findings (which may emerge over time):

• End-organ resistance to several endocrine hormones:
  • Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
  • Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
  • Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
    In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
  • Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
  • Calcitonin, with asymptomatic hypercalcitonemia
  • CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
    Note: Many affected individuals have normal neurocognitive function.
• Albright hereditary osteodystrophy (AHO) phenotype:
  • Short stature
  • Round facies
  • Subcutaneous ossifications
  • Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
    Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
  • Intrauterine growth restriction

Pseudohypoparathyroidism Ib (PHP-Ib). Suggestive findings include:

• PTH resistance, the principal endocrine abnormality
• In some affected individuals:
  • Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [Levine 2012]
  • Mild brachydactyly (despite absence of the classic AHO phenotype)
  • Enhanced intrauterine growth [Bréhin et al 2015] (See Table 2.)
  • Madelung deformity [Sanchez et al 2011]

Pseudopseudohypoparathyroidism (PPHP), a more limited form of PHP-Ia, involves various manifestations of the AHO phenotype without hormone resistance or obesity.

Progressive osseous heteroplasia (POH), a more restricted variant of PPHP, consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia [Kaplan et al 1994].

Osteoma cutis (OC), another more restricted variant of PPHP, consists of extraskeletal ossification limited to the dermis and subcutaneous tissues.

Establishing the Diagnosis

The diagnosis of a disorder of GNAS inactivation is established in a proband with all or some of the above clinical findings and evidence on molecular genetic testing of a genetic or epigenetic alteration resulting in lack of expression/function of the GNAS complex locus. See Table 1 for a summary of molecular genetic testing, Table 2 for a summary of the phenotypes and genetic mechanisms of disorders of GNAS inactivation, and Molecular Genetics for details of the GNAS molecular defects.

The PHP-Ia, -Ib, and -Ic phenotypes are associated with lack of expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) as a result of one of the following:

• An inactivating GNAS pathogenic variant
• A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus
• Isolated epimutations [Takatani et al 2015]
• Uniparental paternal 20q disomy [Takatani et al 2015]

The PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα (encoded by the paternal GNAS allele) due to an inactivating GNAS pathogenic variant; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal GNAS allele) caused by an inactivating GNAS pathogenic variant.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because of the varied manifestations of the disorders of GNAS inactivation, individuals with the findings of one of the distinctive phenotypes described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with clinical findings indistinguishable from other inherited disorders with similar endocrine abnormalities are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the clinical and endocrine findings suggest one of the distinctive phenotypes, molecular genetic testing approaches can include single-gene testing and methylation analysis or use of a multigene panel.

Single-gene testing and methylation analysis

• Single-gene testing. Sequence analysis of exons 1 through 13 of GNAS is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  Note: In persons with the PHP-Ib phenotype, STX16 deletion/duplication analysis should be performed if no GNAS pathogenic variant is identified and if methylation defects are limited to GNAS exon A/B differentially methylated region (DMR) (also referred to as exon 1A or GNAS A/B:TSS-DMR).
• Methylation analysis examines differentially methylated regions (DMRs) of the GNAS complex locus for loss of the normal methylation pattern on the maternal allele (i.e., an imprinting defect). When a GNAS pathogenic variant is not identified on sequence analysis, it is appropriate to perform methylation analysis. Note: Although loss of methylation can identify the presence of an imprinting defect, it cannot identify the cause of the imprinting defect.
  PHP-Ia. In some instances, individuals with PHP-Ia may have partial methylation defects of uncertain significance.
  PHP-Ib. Because alterations of various imprinting control regions are associated with PHP-Ib, loss of methylation at the exon A/B DMR of the maternal GNAS complex locus is observed in all affected individuals; thus, methylation analysis should be the initial test in individuals with findings suggestive of PHP-1b.
  • Familial PHP-Ib is in most instances caused either by multiexon deletions disrupting the upstream gene STX16 or (less frequently) by deletions involving NESP (Figure 1) [Elli et al 2014a].
  • Sporadic PHP-Ib. The genetic basis for the methylation defect in sporadic PHP-Ib is usually unknown; however, broad GNAS imprinting abnormalities involving multiple DMRs have been observed in most affected individuals, some of whom had molecular genetic findings consistent with paternal uniparental 20q isodisomy [Takatani et al 2015] (Table 2).
    Note: in some cases, deletions encompassing the whole GNAS complex locus can mimic methylation defects associated with sporadic PHP-Ib. In case of an overall methylation defect, deletion/duplication analysis should be performed.

Figure 1.

Schematic of the GNAS complex locus and nearby gene, STX16. GNAS exons 1-13 encode Gsα. See Additional transcripts of the GNAS complex locus (pdf) for more details about GNAS alternative first exons. STX16 is centromeric to the GNAS complex locus (more...)

Multigene panel

• A multigene panel that includes GNAS and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. These approaches do not allow the characterization of imprinting defects.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from other inherited disorders with similar endocrine abnormalities, comprehensive genomic testing (exome sequencing or genome sequencing) can be considered.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Genomic testing does not allow characterization of imprinting defects.

Table 1.

Molecular Genetic Testing Used in Disorders of GNAS Inactivation

Clinical Description

Disorders of GNAS inactivation include pseudohypoparathyroidism Ia (PHP-Ia), Ib (PHP-Ib), and Ic (PHP-Ic), as well as pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC) (see Table 2).

The term pseudohypoparathyroidism (PHP) refers to disorders with hypocalcemia and hyperphosphatemia (which are typical of hypoparathyroidism) that result from end-organ resistance to ‒ rather than deficiency of ‒ parathyroid hormone (PTH).

Phenotypes and Genetic Mechanisms of Disorders of GNAS Inactivation

Table 2 summarizes the different phenotypes that result from disorders of GNAS inactivation. Note the various molecular defects and associated parental origin. See Molecular Genetics and Figure 1 for a description and map of the GNAS complex locus and the upstream gene, STX16.

Table 2.

Phenotypes and Genetic Mechanisms of Disorders of GNAS Inactivation

Genotype-Phenotype Correlations

No clear correlation appears to exist between the type and location of GNAS complex locus / STX16 pathogenic variants and disease onset, severity of endocrine resistance, or number of AHO features.

However, two unique variants affecting both the stability and the activity of Gsα have been described in three unrelated individuals with PHP1a who presented with additional clinical features reflecting enhanced Gsα activity:

• A missense variant associated with typical PHP1a features as well as testotoxicosis [Nakamoto et al 1996]
• A four amino-acid insertion within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had germline mosaicism [Aldred et al 2000]. Biochemical and intact cell studies suggested that the phenotype results from Gsα deficiency due to instability of the mutated protein and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine [Makita et al 2007].

Penetrance

Disorders of GNAS inactivation show complete penetrance, with manifestations typically appearing during childhood. However, the exact manifestations and severity vary significantly among individuals.

Prevalence

The estimated prevalence for pseudohypoparathyroidism (PHP) and Albright hereditary osteodystrophy (AHO) is approximately 0.79 per 100,000 (according to the Orphanet Report Series, November 2008).

A Japanese study estimated the prevalence of PHP at 3.4 per 1 million individuals [Nakamura et al 2000].

The prevalence of POH has never been estimated. It is likely extremely rare: fewer than 60 clinically confirmed individuals worldwide have been reported [Shore & Kaplan 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a disorder of GNAS inactivation, the following evaluations are recommended:

• Assessment of height, weight, body mass index, growth velocity, and pubertal development
• X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced
• Endocrinology evaluation, with studies that may include the following:
  • Serum concentration of calcium and phosphorous
  • Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
  • Parathyroid hormone (PTH)
  • Thyroid-stimulating hormone (TSH) and free T4
  • Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
  • Urinary calcium excretion and tubular reabsorption of phosphorus
    Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Psychoeducational profile/developmental assessment
• Ophthalmologic examination for cataracts
• Consultation with nutritionist when obesity is present
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hypocalcemia. Therapy of hypocalcemia is similar to the treatment of other forms of hypoparathyroidism: restoring serum calcium to the normal level using supplemental calcium (1-2 grams or 25-50 mg/kg of elemental calcium per day) and activated forms of vitamin D (calcitriol or 1-alpha calcidiol).

For all forms of PHP-I, calcium and activated vitamin D doses should be adjusted to try to maintain PTH levels at the upper limit of normal or even slightly higher (e.g., 50-150 pg/mL) to avoid secondary complications of chronic hyperparathyroidism. Urinary calcium excretion should be monitored to detect hypercalciuria; however, because calcium reabsorption in the thick ascending limb of the kidney remains responsive to PTH, hypercalciuria in these individuals is very rare as long as PTH is not suppressed.

Rarely thiazide diuretics can be considered in individuals who develop hypercalciuria.

Maintenance of a normal serum calcium-phosphorus product is recommended to minimize the risk of cataract formation and intracerebral calcification. Oral calcium supplements should be taken with meals to reduce serum phosphorus levels. Occasionally, phosphate-binding resins may be required.

Note: Because individuals with PHP-I do not respond to PTH, there is no role for PTH therapy in these individuals.

Hypothyroidism and gonadotropin resistance are treated in the conventional manner.

Growth hormone deficiency. If screening for growth hormone deficiency with appropriate provocative testing is abnormal, growth hormone replacement therapy should be considered. Note that in small case series treatment with growth hormone replacement increased growth velocity, but did not improve final adult height [Mantovani et al 2010]. Nevertheless, there are suggestions that growth hormone replacement may also have a salutary effect on weight. Failure to improve final adult height may be due to partial resistance to the paracrine effects of PTH-related peptides in growth plate cartilage, accounting for advanced skeletal maturation, premature closure of the epiphyses, and short stature [Bastepe et al 2004].

Subcutaneous ossifications may be surgically removed if they are large or cause local irritation. Ossifications may recur if residua are left in situ. Ossifications may enlarge in individuals treated with growth hormone.

Obesity is the greatest treatment challenge. Current strategies involve the usual recommendations of reduced caloric intake and increased physical activity. Given that individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia, these efforts may be less successful than in persons with obesity from other causes.

Surveillance

Surveillance includes the following:

• Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.
• Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.
• Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications
• Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts
• Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)
• Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function

Agents/Circumstances to Avoid

Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include:

• Molecular genetic testing if the genetic mechanism of GNAS inactivation has been identified in the family (Table 2).
• If the genetic mechanism of GNAS inactivation is not known, at-risk relatives can be assessed by physical examination and regular measurement of serum concentrations of parathyroid hormone (PTH), calcium, and phosphorus.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Serum concentration of calcium and thyroid studies (TSH and free T4) should be monitored throughout pregnancy, labor, and the postpartum period.

Calcium, vitamin D, and thyroid hormone should be supplemented as needed [Singh et al 2012]. Note that requirements for thyroid hormone will increase in early pregnancy, while requirements for activated forms of vitamin D may decline during the third trimester.

Because breastfeeding can significantly reduce requirements for activated vitamin D, mothers should be monitored for this during lactation and after weaning.

Therapies Under Investigation

Dr Emily Germain-Lee at the University of Connecticut is recruiting individuals with PHP-Ia and AHO to determine whether growth hormone therapy can improve short stature and obesity.

Researchers at Vanderbilt University Medical Center are investigating whether theophylline treatment promotes weight loss, improves glucose tolerance, and slows growth plate closure in children and young adults.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele [Lemos &Thakker 2015].

Pseudohypoparathyroidism (PHP) Ia, Ib, and Ic result from reduced or absent expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) due to one of the following:

• An inactivating GNAS pathogenic variant
• A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus
• Isolated epimutations
• Paternal 20q disomy

The PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal GNAS allele due to an inactivating GNAS pathogenic variant; the POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the maternal GNAS allele due to an inactivating GNAS pathogenic variant.

Risk to Family Members

Of individuals with a disorder of GNAS inactivation, approximately 38% have an affected parent and 38% have a de novo GNAS pathogenic variant; in the remaining approximately 25% the cause is unknown [Elli et al 2016].

Table 3.

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

Offspring of a proband with a disorder of GNAS inactivation. Each child of an individual with a disorder of GNAS inactivation has a 50% chance of inheriting the genetic alteration, except for persons with simplex PHP-1b, in which there may not be an underlying heritable variant. The phenotype of the offspring who inherit a GNAS pathogenic variant or imprinting defect depends on the sex of the parent of origin (see Table 4).

Table 4.

Disorder of GNAS Inactivation: Phenotypes for Offspring Based on the Sex of the Parent

Note regarding inheritance of PHP-Ib: Although females who inherit a PHP-Ib-related genetic alteration from their father (i.e., a paternally imprinted PHP-Ib-related genetic alteration) will be unaffected, their offspring have a 50% risk of inheriting the now maternally imprinted PHP-Ib-related genetic alteration and being affected.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the mechanism of GNAS inactivation has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a disorder of GNAS inactivation and preimplantation genetic testing are possible.

The phenotype in offspring who inherit a GNAS pathogenic variant depends on the sex of the parent of origin (i.e., the parent from whom an individual inherited the GNAS pathogenic variant; see Risk to Family Members, Offspring of a proband with a disorder of GNAS inactivation).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The PHP-Ia, Ib, Ic phenotypes are associated with lack of expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) as a result of one of the following:

• An inactivating GNAS pathogenic variant
• A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus
• Isolated epimutations
• Paternal 20q disomy

PPHP is associated with lack of expression/function of Gsα encoded from the paternal GNAS allele with an inactivating GNAS pathogenic variant. POH/OC is also most commonly associated with paternal GNAS pathogenic variants.

Pathogenic Variants

PHP-Ia and PHP-Ic and PPHP or POH/OC. Although the inactivating GNAS pathogenic variants observed in the phenotypes PHP-Ia and PHP-Ic and the phenotypes PPHP or POH/OC are similar, they differ in the parent of origin (Table 2):

• PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
• PPHP result from lack of expression of the paternal allele.
• POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.

PHP-Ib. The genetic alteration differs in familial cases and simplex cases (i.e., a single occurrence in a family) (Table 2).

Familial PHP-Ib genetic alterations include:

• A pathogenic GNAS variant in exon 13 on the maternal allele;
• Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or GNAS A/B:TSS-DMR);
• Deletion of maternal STX16 exons 3-5 or 4-6 [Bastepe et al 2003, Linglart et al 2005];
• Deletion of maternal NESP and/or NESP-AS [Bastepe et al 2005, Chillambhi et al 2010, Richard et al 2012, Rezwan et al 2015];
• Deletion of maternal STX16 [Elli et al 2014b, Tafaj & Jüppner 2017].

Simplex PHP-Ib genetic alterations include:

• GNAS imprinting abnormalities that involve multiple DMRs [Mantovani et al 2012];
• Paternal uniparental disomy for all or part of chromosome 20 [Fernandez-Rebollo et al 2010, Linglart et al 2013].

General comments. The most commonly found GNAS variants are frameshift, nonsense, or splicing; they are expected to lead to untranslated proteins. Nonsense and single-nucleotide variants that alter translation initiation or mRNA splicing have also been documented [Elli et al 2013a, Elli et al 2016].

Heterozygous GNAS pathogenic variants in exon 1 are the most common (18%). Only one individual has been described with a pathogenic variant in exon 3, which is alternatively spliced out of transcripts that encode a slightly smaller form of Gsα [Thiele et al 2007]. While pathogenic variants are distributed across GNAS [Mantovani et al 2016], exon 7 is a hot spot for the 4-bp GNAS deletion c.565_568delGACT [Elli et al 2013a].

Individuals with pathogenic variants in exon 1 of GNAS have a higher prevalence of ectopic ossifications than other affected individuals [Elli et al 2013a]. Truncating variants are associated with more ectopic ossifications than other types of pathogenic variants [Lemos & Thakker 2015, Thiele et al 2015].

Table 5.

GNAS Pathogenic Variants Discussed in This GeneReview

Author Notes

Dr Levine's web page

Revision History

• 26 October 2017 (bp) Review posted live
• 15 April 2015 (mal) Original submission

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