Disorders Of Gnas Inactivation

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Summary

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.

Diagnosis

No specific clinical criteria establish the diagnosis of a disorder of GNAS inactivation.

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 or 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.
Figure1. . Schematic of the GNAS complex locus and nearby gene, STX16.

Figure1.

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 at the most reasonable cost 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

Gene 1MethodProportion of Probands with a Diagnostic Change 2 Detectable by Method
GNASSequence analysis 362%-82% 4
Gene-targeted deletion/duplication analysis 510 deletions reported to date 6
Methylation analysis 710%-60% (virtually 100% for PHP-Ib) 4
Chromosomal microarray analysis 810% 9
STX16Gene-targeted deletion/duplication analysis 5See footnote 10
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Ahrens et al [2001], Linglart et al [2002], Shore et al [2002], Mantovani et al [2010], Elli et al [2013a], Takatani et al [2015]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Includes: two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and postnatal growth retardation and clinical manifestations suggestive of PPHP [Geneviève et al 2005]; a female with PHP-Ia and a 30-kb deletion (including GNAS exons 1-5) inherited from her mother, who was mosaic for this heterozygous deletion [Fernandez-Rebollo et al 2010]; brothers with PHP-Ia and an 850-kb deletion (involving all of GNAS as well as other genes) that was inherited from their mother, who had PPHP [Mitsui et al 2012]; and seven novel genomic deletions ranging from 106 bp to 2.6 Mb in families with PHP-Ia [Garin et al 2015]

7.

Methylation analysis examines differentially methylated regions (DMRs) of the GNAS complex locus for loss of the normal methylation pattern on the maternal allele.

8.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the GNAS complex locus/STX16 region. Note: The GNAS complex locus/STX16 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.

9.

Includes UPD(20q)pat [Fernandez-Rebollo et al 2010, Linglart et al 2013]

10.

Relevant for testing those with the PHP-Ib phenotype who: do not have an identified maternal GNAS pathogenic variant; and do have a methylation defect at exon A/B DMR (also referred to as exon 1A or GNAS A/B:TSS-DMR)

Clinical Characteristics

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).

Pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ic

PHP-Ia and PHP-Ic have a similar phenotype and are distinguished only by ex vivo assays of Gsα protein function that are based on hormone receptor activation of Gsα; in these assays Gsα activity is reduced by approximately 50% in PHP-Ia and normal in PHP-Ic (Table 2).

Endocrine. The clinical phenotype consists of metabolic resistance to multiple endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), calcitonin, and often gonadotropins [Levine 2012]. The most common endocrinopathies are biochemical hypoparathyroidism, primary hypothyroidism (without goiter), and growth hormone deficiency (demonstrated in 50%-70% of affected individuals) [de Sanctis et al 2007]. Obesity, due to decreased resting energy expenditure [Roizen et al 2016], appears to result from impaired Gsα-coupled signaling in imprinted regions of the hypothalamus (which, based on mouse studies, is likely to be in the dorsomedial hypothalamus) [Chen et al 2017].

The development of the endocrine features occurs over time. The earliest manifestation of hormone resistance is usually mild hypothyroidism, which is often discovered during newborn screening as an elevated TSH with normal serum levels of thyroid hormones. The average age at diagnosis of PHP-Ia is around age seven years, when PTH resistance and hypocalcemia are recognized; however, individuals with milder manifestations may not be diagnosed until the third decade of life [Linglart et al 2013, Turan & Bastepe 2015].

  • TSH resistance is variable and may manifest as congenital hypothyroidism; however, TSH may be elevated in individuals who are euthyroid, or only after formal TRH stimulation testing. Serum levels of thyroid hormone are usually normal or only mildly depressed.
  • PTH resistance. Although random PTH levels are often elevated in PHP-Ia, hypocalcemia may fluctuate and may not become clinically significant until later childhood. Hyperphosphatemia usually precedes hypocalcemia. Some individuals remain eucalcemic.
    Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)2D, the active form of vitamin D, in response to the elevated levels of circulating PTH that result from decreased ability to excrete urinary phosphate [MA Levine, personal observation].
    As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
    Bone density is often increased [Long et al 2010].
    Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [Fitch 1982]. Cataracts can also be seen in the setting of prolonged hypocalcemia.
  • Gonadotropin resistance may result in delayed puberty and incomplete development of secondary sex characteristics, menstrual irregularities, or reduced fertility.
  • Early-onset morbid obesity can begin in infancy [Dekelbab et al 2009]. At least 65% of those younger than age 18 years are obese [Fitch 1982].

Sleep apnea is also common (45% of individuals), but is only partly explained by obesity, as individuals with PHP-Ia have a fourfold increased risk for sleep apnea compared to similarly obese individuals. This increase may be due to hypotonia as well as the effects of Gsα inactivation on the normal sleep cycle [Landreth et al 2015].

Musculoskeletal. At birth growth parameters are usually normal, but can be below normal [Wilson 2006]; however, neonates may then present with congenital hypothyroidism or ectopic ossifications.

Linear growth may initially be normal or advanced due to obesity; bone age is frequently advanced beyond chronologic age [Fitch 1982]. Linear growth slows soon after early childhood and prematurely ceases in early puberty, leading to height below the third percentile in the majority of adults [Fitch 1982, Wilson 2006] primarily due to premature closure of epiphyseal growth plates; however, GH deficiency may also be a contributing factor.

Affected individuals display clinical features of Albright hereditary osteodystrophy (AHO) comprising a round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification of the dermis and subcutaneous tissues. Macrocephaly relative to height is typical: 40% have a head circumference above the 90th percentile [Fitch 1982, Wilson 2006].

The most common musculoskeletal feature is brachydactyly; brachydactyly type E is manifest as shortened metacarpals (particularly 4th and 5th) and metatarsals (particularly 3rd and 4th) plus brachydactyly type D, manifest as shortening of the distal phalanx of the thumb.

Even in the absence of brachymetacarpia, individuals with AHO usually have brachydactyly type D, a shortened distal thumb phalanx and short, broad thumbnails, associated radiographically with cone-shaped epiphyses [Fitch 1982].

Brachydactyly may lead to carpal tunnel syndrome with symptomatic paresthesia, which may be confused with the symptoms of hypocalcemia [Joseph et al 2011].

Other reported musculoskeletal features include craniosynostosis, hyperostosis of the cranial vault, absence of normal caudal widening of the lumbar interpedicular distances (associated with spinal stenosis), ossification of paravertebral ligaments, shortened distal ulnas, bowing of the tibia and radius, small capital femoral epiphyses, coxa vara, coxa valga, increased prevalence of bony exostoses, and carpal tunnel syndrome [Wilson & Hall 2002, van Lindert et al 2008, Joseph et al 2011].

Skin. Ectopic ossifications (also known as osteoma cutis) are true heterotopic intramembraneous bone which occur in 60%-70% of affected individuals, independent of calcium, phosphate, or PTH levels [Prendiville et al 1992].

Ectopic ossifications are most commonly cutaneous, either within subdermal fat or in the dermis. They are located most commonly in the scalp and extremities (particularly the periarticular areas of the hands and feet). These lesions may be very small and asymptomatic, or painful; occasionally lesions can extrude a chalky material. Removal of ectopic ossifications does not result in progression or exacerbation although they may recur if removal is incomplete [Fitch 1982, Prendiville et al 1992, Wilson 2006].

Other areas of ectopic ossification include the sclera and choroid of the eye and cardiac ventricular septum. Visceral involvement is rare [Fitch 1982].

Dental changes such as enamel hypoplasia, widened root canals, shortened roots with open apices, thickened laminar dura, and delayed dental eruption have been noted in more than 30% of affected individuals, often with impacted second molars [Ritchie 1965].

Mild to moderate intellectual disability is seen in up to 79% of affected individuals [Mouallem et al 2008].

Pseudohypoparathyroidism Ib (PHP-Ib)

PHP-Ib consists of PTH resistance with partial resistance to TSH in some affected individuals. Partial TSH resistance manifests as slightly elevated serum TSH levels with generally normal (or low) serum concentrations of thyroid hormones [Levine 2012].

Poorly treated PTH resistance can lead to hyperparathyroid bone disease or tertiary hyperparathyroidism. Very rarely bone density can be elevated [Sbrocchi et al 2011].

Patterns of excessive growth or weight gain have been described in newborns or during early infancy and childhood.

Individuals with PHP-Ib may have growth-plate defects such as mild brachydactyly or a Madelung deformity-like defect [Sanchez et al 2011], but lack the complete constellation of features seen in AHO. Intellect is typically normal.

The average age of diagnosis for symptomatic individuals is age ten to 12 years [Linglart et al 2007], which is later than for PHP-Ia.

Pseudopseudohypoparathyroidism (PPHP)

The phenotype is heterogeneous with a wide differential diagnosis (see Differential Diagnosis).

Intrauterine growth restriction is common.

Ectopic ossifications are frequent and almost pathognomonic of Gsα deficiency.

Individuals with PPHP have normocalcemia and no endocrine defects, but have the physical phenotype of Albright hereditary osteodystrophy.

Obesity and intellectual disabilities (10%) are less prevalent than in PHP-Ia [Long et al 2007, Mouallem et al 2008].

Progressive Osseous Heteroplasia (POH)

Individuals with POH have no endocrine defects or features of AHO, but have progressive ectopic ossification that extends to deep connective tissues, often with debilitating effects [Levine 2012, Pignolo et al 2015].

Of note, POH-like ossifications have been observed rarely in individuals with AHO or PHP-1a.

Osteoma Cutis (OC)

Individuals with OC develop ossification limited to the dermis and subcutaneous tissues.

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

PhenotypeEndocrine DefectsClinical FeaturesOther FeaturesParental Origin of the Inactivated GNAS AlleleMolecular Defect 1
PHP-IaMultihormone resistance 2AHO 3; early-onset obesityCognitive disabilityMaternalHeterozygous GNAS pathogenic variant in exons 1-12 4, 5
PHP-IcMultihormone resistance 2AHOCognitive disabilityMaternalHeterozygous GNAS pathogenic variant in exon 13 6
PHP-IbPTH resistance; partial TSH resistance in someEnhanced intrauterine growth 7; mild brachydactyly in someLoss of methylation in exon A/B 1, 7 (familial)MaternalImprinting defect: heterozygous deletion of STX16 or regulatory elements in GNAS complex locus 1, 8 (familial)
Variable degrees of a more global defect in methylation at multiple DMRs 3, 4 (sporadic)Paternal 20q disomy or unknown epigenetic defect (sporadic) 4
PPHPNoneAHO; IUGR 9PaternalHeterozygous GNAS pathogenic variant 4, 5
Progressive osseous heteroplasiaNoneProgressive heterotopic ossification extending to deep connective tissuesPaternalHeterozygous GNAS pathogenic variant 4
Osteoma cutisNoneHeterotopic ossification limited to dermis & subcutaneous tissuesPaternalHeterozygous GNAS pathogenic variant 4

From Levine [2012]

AHO = Albright hereditary osteodystrophy; DMR = differentially methylated region; IUGR = intrauterine growth restriction; PHP = pseudohypoparathyroidism; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone

1.

See Molecular Genetics and Figure 1 for details of the structure and expression of the GNAS complex locus.

2.

Multiple hormone resistance, resistance to PTH, TSH, and GHRH; often gonadotropins (LH and FSH) as well

3.

AHO comprising round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification

4.

Takatani et al [2015]

5.

Chromosome abnormalities of GNAS-related disorders are uncommon; however, Aldred et al [2002] described two individuals with full deletions of GNAS due to interstitial chromosome deletions: one with a maternally derived deletion of chromosome 20q13.31-q13.33 and a diagnosis of PHP-Ia and the other with a paternally inherited deletion of chromosome 20q13.13-q13.32 and a diagnosis of PPHP.

6.

Impairs coupling of Gsα to heptahelical receptors. See Molecular Genetics.

7.

Bréhin et al [2015]

8.

STX16 and DMRs associated with GNAS exons designated NESP and GNAS-AS1. See Figure 1; Elli et al [2013a] and references therein.

9.

Associated mainly with pathogenic variants in GNAS exons 2-13 [Richard et al 2013]

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].

Differential Diagnosis

Conditions to be considered in the differential diagnosis include the following:

  • 2q37 deletion syndrome, which is characterized by mild-moderate developmental delay/intellectual disability, brachydactyly of digits 3-5 (often digit 4 alone), short stature, obesity, hypotonia, round facies, behavioral abnormalities, joint hypermobility/dislocation, and scoliosis. Affected individuals have normal endocrine function, however. In most individuals with the 2q37 deletion syndrome, the deletion is de novo. This condition can also be associated with heterozygous pathogenic variants in HDAC4.
  • Idiopathic or primary hypoparathyroidism, resulting from decreased parathyroid function, can have many causes including hypo- or aplasia of the parathyroid gland or autoimmune-related damage. Symptoms include cramping and twitching of the muscles (tetany), paresthesias, fatigue, and abdominal pain. PTH and calcium levels are low and phosphorous levels are elevated.
  • Kenny-Caffey syndrome (OMIM 127000, 244460) is characterized by proportionate short stature, cortical thickening and medullary stenosis of the tubular bones