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Francesca Marta Elli, MSc, PhD, Arrate Pereda, MSc, PhD, Agnès Linglart, MD, PhD,
Guiomar Perez de Nanclares, MSc, PhD, Giovanna Mantovani, MD, PhD
PII: S1521-690X(18)30108-8
DOI: 10.1016/j.beem.2018.09.008
Reference: YBEEM 1242
To appear in: Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Elli FM, Pereda A, Linglart A, de Nanclares GP, Mantovani G, Parathyroid
hormone resistance syndromes – Inactivating PTH/PTHrP Signaling Disorders (iPPSDs), Best
Practice & Research Clinical Endocrinology & Metabolism (2018), doi: https://doi.org/10.1016/
j.beem.2018.09.008.
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Best Practice and Research Clinical Endocrinology and Metabolism
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Francesca Marta Elli, MSc, PhD
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Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit; Department of Clinical
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email francesca.elli@unimi.it ; phone +39 02 55033512 ; fax +39 02 55033361
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Arrate Pereda, MSc, PhD (co-first author) AN
Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital,
Vitoria-Gasteiz, Spain.
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APHP, Department of paediatric endocrinology and diabetes for children, Bicêtre Paris-Sud Hospital, Le
Kremlin-Bicêtre, France,
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APHP, Reference center for rare disorders of calcium and phosphate metabolism, filière OSCAR and
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Plateforme d'Expertise Maladies Rares Paris-Sud, Bicêtre Paris-Sud Hospital, Le Kremlin Bicêtre, France,
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email agnes.linglart@aphp.fr
Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital,
Vitoria-Gasteiz, Spain.
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit; Department of Clinical
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Abstract (max 150 words)
Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of
PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations
Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the
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stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory
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subunit 1A and the phosphodyestarase type 4D.
The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not
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include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so
that a new nomenclature and classification has been recently proposed grouping these disorders under the
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term “inactivating PTH/PTHrP signaling disorder” (iPPSD).
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This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous
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Key words:
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Hormone resistance
Pseudohypoparathyroidism (PHP)
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GNAS
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PRKAR1A
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PDE4D
PDE3A
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1. Introduction
The non-responsiveness of target organs to a specific hormone usually derives from molecular alterations
affecting hormone receptors, while pathologic features caused by multiple hormone resistance arise from the
Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands and is a key modulator of
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mineral homeostasis. Its deficiency leads to hypocalcemia as key clinical and biochemical characteristic.
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In clinical practice, the diagnosis of PTH resistance, usually referred to as Pseudohypoparathyroidism (PHP),
is defined by the co-existence of elevated serum levels of parathyroid hormone (PTH), low or normal
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calcemia, elevated phosphatemia, normal renal function, normal magnesium levels and in absence of vitamin
D deficiency. Besides cramps, seizures and neuromuscular consequences of hypocalcemia, the clinical
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manifestations of PTH resistance are the intracranial calcifications of the basal ganglia and cataracts due to
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the combination of long-standing of chronic hypocalcemia and hyperphosphatemia. PTH resistance can be
definitively ascertained using recombinant PTH (1–34), the Ellsworth-Howard test or a subcutaneous
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challenge (1).
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Over the last few decades our understanding on both the molecular basis and the clinical manifestations of
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disorders whose hallmark is PTH resistance has deeply expanded. This review will summarize the current
The serum calcium level regulates PTH secretion via a negative feedback through the parathyroid calcium
sensing receptor (CASR). Decreased calcium levels stimulate PTH release. Secreted PTH interacts with its
specific G-protein-coupled receptor (GPCR), the type 1 receptor (PTHR1), which is highly expressed in
bone and kidney and mediates the rapid increases in renal tubular reabsorption of calcium and decreased
calcium and phosphorus from bone and increasing renal synthesis of 1,25-dihydroxy vitamin D, which, in
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turn, increases intestinal calcium absorption (2-4). The PTHR1 also mediates the paracrine actions of PTH-
related protein (PTHrP), which plays a particularly vital role in the process of endochondral bone formation.
GPCRs activate a superfamily of heterotrimeric guanine nucleotide binding proteins called G proteins, that
trigger the activation of downstream effectors (enzymes and ion channels) inducing both short-term effects
on hormone secretion, neurotransmission and muscle contraction and long term effects on gene transcription
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(5-9). The specificity of G proteins depends on the alpha subunit, which vary in range of expression and
selectivity of receptor-effector coupling. The alpha subunit of the stimulatory G protein (Gsα) is a key
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element of the cAMP-mediated signaling, which stimulates the cAMP formation and the subsequent protein
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kinase A (PKA) activation (Figure 1).
In human disease, the impairment of the Gsα/cAMP/PKA pathway mostly affects the signaling of
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PTH/PTHrP, and, with different severity, the signaling of additional hormones, including TSH, GHRH,
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calcitonin and gonadotropins, so their resistance can be detected at different stages of life in the patients,
The loss of Gsα signaling in the kidney, in particular in proximal tubular cells, is the crucial event leading to
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PTH resistance. In most patients, PTH resistance develops during infancy or childhood. The most accepted
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hypothesis to explain this latency in PTH resistance development is the temporary physiological biallelic
expression of maternal and paternal Gsα alleles renal proximal tubules during early postnatal development
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and/or the rescue of the cAMP/PKA signaling XLαs, the extra-large splice variant of Gsα that is expresed in
It is proposed that the conserved anticalciuric action exerted at the level of the distal tubule allows most
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patients to preserve normo-hypocalciuria and life-long normal renal function without forming kidney stones
(25).
The defective generation of 1,25-dihydroxyvitamin D caused by the defective signaling of PTH, further
In clinical practice, the diagnosis of TSH resistance is defined by the detection of elevated TSH levels, with
normal/slightly low free thyroxine levels, usually in the absence of goiter and antithyroid antibodies. It may
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develops over childhood or adolescence, although it is seldom detected during the neonatal screening for
women are manifestations of gonadotropins resistance (17). The GH deficiency derived from GHRH
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After an extensive review of the literature and discussion about a novel classification/nomenclature to
describe disorders related to abnormalities of the PTH signaling pathway, a proposal to group these
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disorders, previously referred mainly to as Pseudohypoparathyroidism, under the term “inactivating
PTH/PTHrP signaling disorder” (iPPSD) has recently been published (Table 1) (26). We will use this
The classical PTH/PTHrP receptor, otherwise known as PTHR1, binds intact PTH and biologically active
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amino-terminal fragments of PTH, such as PTH 1-34 (27). It recognizes both PTH and PTHrP due to the
substantial degree of homology in the amino-terminal parts of these two peptides. This receptor is heavily
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expressed in bone and kidney and is also present in additional tissues such as breast, skin, heart, blood
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vessels, pancreas, and others that are not regarded as classical PTH target tissues (28).
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Mutations of the PTHR1 gene (MIM*168468), lying on the short arm of the chromosome 3 (3p21.31), are
associated with the iPPSD1 cluster (i.e., Blomstrand chondrodysplasia (BOCD, MIM#215045) and the Eiken
BOCD is a lethal form of dwarfism (short limbs, polyhydramnios, hydrops fetalis, facial anomalies,
increased bone density and advanced skeletal maturation) and the Eiken syndrome is a skeletal dysplasia
(retarded bone maturation, principally of the epiphyses, pelvis, hands and feet) with slightly elevated levels
form, while the type 2, which derives from an incomplete inactivation of PTHR1, is associated with a
slightly less severe phenotype. So far only 5 pathogenetic genetic variants have been reported in exon 5
(c.310C>T), exon 6 (c.395C>T), intron 11 (c.1049+27G>A), exon 12 (c.1093del) and exon 13 (c.1148G>A).
Nowadays, only 1 variant in exon 16 (c.1453C>T, p.Arg485*) associated with the Eiken syndrome has been
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described (29-31).
All reported sequence are described following the Human Genome variation Society (HGVS)
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recommendations according with the reference transcript NM_000316.2 and are recorded in the publicly
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available Leiden Open Variation Database (LOVD) database at
https://databases.lovd.nl/shared/genes/PTH1R.
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Heterozygous PTHR1 mutations have identified in patients with primary failure of tooth eruption (33-34).
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3.2. PTHR2
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The PTH receptor 2 (PTHR2) selectively binds PTH but not PTHrP (28). It is heavily expressed in the
central nervous system, cardiovascular, and gastrointestinal systems, as well as in lung and testes, and may
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An intronic break of the PTHR2 gene was detected by whole genome sequencing in a 15-month-old boy with
sagital and metopic synostosis. The disruption of the PTHR2 gene may cause uncontrolled proliferation and
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differentiation of chondrocytes, which in turn results in premature closure of sutures (32). Experiments with
transgenic mice suggest a role for PTHR2 signaling in postnatal growth plate development and subsequent
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bone mass acquisition as overexpression of human PTHR2 in chondrocytes of these mice has key
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Molecular defects affecting different members the PTH/PTHrP pathway are associated with a group of
heterogeneous but related disorders that represent a challenge for differential diagnosis and genetic
counseling. As the defects are affecting the pathway, not only PTH resistance, but also resistance to other
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hormones (TSH, gonadotropins, GHRH and probably others) that mediate their action through GPCR
In particular, genetic defects at the gene coding the Gsα determine a clinical condition classified as iPPSD2
(encompassing the previously named PHP type 1A and 1C, pseudopseudohypoparathyroidism, Progressive
Osseous Heteroplasia and Osteoma Cutis) whereas epigenetic defects at the same locus are causative of
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iPPSD3 (previously termed PHP type 1B). Alterations of other downstream molecular effectors, including
the Protein Kinase cAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A) and the
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Phosphodiesterase 4D (PDE4D), cause iPPSD4 and iPPSD5 (previously defined as ACRDYS1 and
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ACRDYS2, being ACRDYS the acronym for acrodysostosis) whereas genetic variants affecting the
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4.1 Genetic defects at the Gsα coding gene cause iPPSD2
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The cluster named iPPSD2 comprises Pseudohypoparathyroidism type 1A (PHP1A, MIM103580),
PHP1A patients are characterized by features of Albright Hereditary Osteodystrophy (AHO) and resistance
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to hormones acting through GPCRs (PTH, TSH, gonadotropins and GHRH), with important interindividual
variability in severity and time course (10-13, 37, 41-44). Patients develop hyperphosphatemia,
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hypocalcemia and elevated PTH over the first years of life (10). Hypothyroidism may be detected at neonatal
screening and, in most cases, patients develop mild resistance to TSH with normal/slightly low thyroid
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hormone levels early in infancy, sometimes over childhood or adolescence, often being already present at the
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time of PTH resistance detection (14-16). Female patients usually present delayed or incomplete sexual
levels and hypogonadism has been confirmed (17). In about two third of investigated patients resistance to
PHP1C is clinically indistinguishable from PHP1A, and, at present, the differential diagnosis depends on the
detection of a normal Gsα activity in the membranes of erythrocytes, fibroblasts and platelets of PHP1C
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patients, a technique available in very few laboratories, not validated for diagnostic use, and does not add
In PPHP, AHO occurs in the absence of endocrine abnormalities and may present both sporadically or
coexist with PHP1A in the same family but never in the same sibship (46-49).
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skeletal muscle and deep connective tissues, whose location and extension are extremely variable. The
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ectopic bone formation begins as a primary osteoma cutis within the dermis at birth or during infancy, then it
extends into subcutaneous and deep connective tissues during childhood (50-52). Recently, POH patients
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showing also AHO features and growth disturbances during the prime infancy have been reported (51-56).
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iPPSD2 is caused by inactivating mutations affecting Gsα coding exons, encoded by the GNAS gene (MIM
*139320; 20q13.2-13.3), that lead to a partial deficiency of a reduction in the Gsα activity in the membranes
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of various cell types (erythrocytes, fibroblasts, platelets). Mutations at the maternal allele are associated with
PHP1A and PHP1C, whereas the same mutations, when affecting the paternal allele lead to PPHP or POH
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Since the description of the first GNAS inactivating mutation in 1990, more than 200 variants (both point
mutations and small/large deletions or insertions) distributed through the gene have been discovered. Most
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defects are private mutations, and the few recurring ones derive from a common molecular mechanism rather
than from a founder effect. The only known mutational hot spot is the c.568_571del deletion in exon 7. All
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GNAS exons are affected with different frequency, with the exception of exons 1 and 7 that host about 20%
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Due to the autosomal dominant inheritance of GNAS defects, offsprings of iPPSD2 patients have a 50%
recurrence risk and depending on the involved allele the clinical outcome will be different (PHP1A/PHP1C
versus PPHP/POH). The detection of pathogenetic variants provides the possibility of predictive genetic
transcript NM_001077488.2, are recorded in the in the publicly available LOVD database at
https://databases.lovd.nl/shared/genes/GNAS.
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iPPSD3 is characterized by PTH renal resistance, frequently also TSH resistance, in the absence of other
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physical abnormalities. Recently, also the impairment of the GHRH-R signaling was proposed as GH
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Common complications of chronic hypocalcemia together with hyperphosphatemia are basal ganglia
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calcifications and cataracts.
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The iPPSD3 subgroup includes disorders associated with changes in the methylation pattern of GNAS
differentially methylated regions (DMRs), including primary epigenetic defects (both severe and partial
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broad GNAS loss of imprinting) and conditions secondary to uniparental disomy of the paternal chromosome
20 (UPD(20)pat) and to deletions of the imprinting control region located within STX16 and/or NESP55
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DMR (62-71).
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The Gsα expression is subject to tissue-specific imprinting and iPPDS3 patients display a paternal-specific
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patterns of cytosine methylation at GNAS DMRs of their maternally inherited alleles. Most cases are
sporadic, so that only one affected individual in a given family has the defect with no underlying known
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The existence of patients with a partial loss of imprinting supports the hypothesis that this type of epigenetic
defect is of postzigotic derivation and leads to epigenetic mosaicism, which could justify its sporadicity and
Only in a small subset of sporadic patients, the epigenetic defect is associated with UPD(20)pat, whose
recurrence, in the absence of a parental translocation, is expected to be less than 1% (62, 69-71).
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On the other hand, the familial form of the disease has a 50% recurrence risk because it is maternally
transmitted in an autosomal dominant manner. This autosomal dominant form is typically characterized by
an isolated loss of methylation affecting the exon GNAS A/B:TSS-DMR due to microdeletions disrupting the
imprinting control region located into the STX16 gene or, less frequently, by a methylation defect at all
maternal GNAS DMRs caused by deletions removing the NESP55 DMR (63-68).
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4.3. Defects at PKA cause iPPSD4 or iPPSD5
iPPSD4 and iPPSD5 refer to Acrodysostosis type 1 (ACRDYS1, MIM101800) and type 2 (ACRDYS2,
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614613), respectively, that are rare congenital malformation syndromes characterized by skeletal dysplasia
frequently associated with AHO-like features (see section 4.5 for Albright’s hereditary osteodystrophy -
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AHO), such as small broad hands and feet with brachydactyly type E, progressive growth failure with severe
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short stature with cone-shaped epiphyses and early epiphyseal fusion, hypoplasia of the skull and thickened
calvaria, advanced bone age, variable degrees of intellectual, developmental and/or behavioural disabilities
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and facial dysostosis (broad face with widely spaced eyes, maxillonasal hypoplasia and flattening of the
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nasal bridge) (9, 66-70). Additional recurring comorbidities are hearing loss, intracranial hypertension,
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About 65% of ACRDYS1 and about 15% of ACRDYS2 patients present with PTH and TSH resistance, and
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up to 20% of ACRDYS2 patients show an altered response to FSH, cryptorchidism and/or lack of puberal
spurt (73-90).
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iPPSD4 and iPPSD5 derive from autosomal dominant genetic defects, with a 50% recurrence risk in the
offsprings of mutated patients, affecting PRKAR1A (MIM* 188830; 17q24.2) and PDE4D (MIM*600129;
All known variants are mainly private, exept a mutational hot spot in the PRKAR1A gene (c.1102C>T). As
for the PDE4D gene, mutations are confined to single kindreds, with the exception of 4 recurring variants
affecting the catalytic unit (c.803T>C, c.1586A>C, c.1835G>A and c.1850T>C) (78-79, 81, 83-88).
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All known sequence variants, described following the HGVS recommendations according with the reference
transcript NM_002734.4 for the PRKAR1A gene and NM_001165899.1 for the PDE4D gene, are recorded in
https://databases.lovd.nl/shared/genes/PDE4D.
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4.4. PDE3A mutations and iPPSD6
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The iPPSD6 subtype includes the previously named Hypertension with Brachydactyly Syndrome (HTNB,
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hypertension, increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla,
altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated (40).
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Up to now few cases have been described, so there is a lack of a full clinical characterization of this disorder.
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iPPSD6 is associated with genetic variants affecting the PDE3A gene (MIM*123805; 3p21.31).
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Genetic variants detected to date are located in exon 4 (c.1333A>G, c.1334C>A/G, c.1336T>C, c.1339G>A,
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c.1340C>T and c.1346G>A/T) and they increase the hydrolytic activity on cAMP (91).
All known sequence variants, described following the HGVS recommendations according with the reference
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transcript NM_000921.4, are recorded in the in the publicly available LOVD database at
https://databases.lovd.nl/shared/genes/PDE3A.
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Patients with iPPSD2 may present with heterogeneous and nonspecific clinical findings including a
dysmorphic trait such as rounded face, auxological parameters such as decreased growth velocity and/or
short stature and early-onset obesity, variable degrees of mental retardation and/or behavioural defects,
extraskeletal ossifications and brachydactyly, that are collectively described as a clinical entity termed
Albright hereditary osteodystrophy (AHO). Such phenotypic features are frequently observed also in patients
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affected with iPPSD3 (59-64) or iPPSD4 and iPPSD5, making the differential diagnosis even more
Additional musculoskeletal abnormalities that seem to be associated with AHO include the spinal cord
compression and the carpal tunnel syndrome (94-95). In patients affected with iPPSD4 and iPPSD5, cone-
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Recent data suggested that defects affecting the PTH/PTHrP pathway may also affect the intrauterine and
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postnatal growth (96). As a matter of fact, in subjects with the paternally-inherited GNAS disease a growth
retardation leading to low birth weight and length was described, while in subjects affected with the
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autosomal dominant form of the GNAS imprinting disorder an opposite phenotype with increased intrauterine
growth was documented (96-98). In about 15% of all the subjects with acrodysostosys bearing a PRKAR1A
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genetic variant an intrauterine growth retardation was reported, but this percentage is likely to be under-
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estimated, this sign not being systematically collected in most series of the past (78).
As for neurocognitive abnormalities, including mental retardation, developmental delay and emotional
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disorders, frequency and severity are not yet well established in iPPSD2 and iPPSD3 patients. Moreover, an
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apparent discrepancy between the adult (27%) and the pediatric populations (64%) was reported (46, 92).
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About half of PRKAR1A mutated patients and up to 95% of the PDE4D mutated patients (iPPSD4&5)
Heterotopic intramembranous ossifications are one of the most specific features of GNAS mutations. Their
number and extension are highly heterogeneous and can be found on physical examination as palpable hard
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nodules, often limited to the dermis and subcutaneous tissues in iPPSD2 patients but they may deepen and
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Premature closure of the growth plate, associated with coning of the epiphysis, determines the brachydactyly
(shortening of III, IV and V metacarpals, and I distal phalanx), that becomes apparent during
infancy/childhood. Due to its highly variable often asymmetric presentation, it is recommended to construct
the metacarpophalangeal pattern profile after posterioanterior left hand radiographs. Brachydactyly is present
in iPPSD2 and in more than 90% of iPPSD4 and iPPSD5 patients (78, 99).
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Further additional recurring comorbidities, such as hearing loss, recurrent otitis media, intracranial
hypertension, shypodeformity of knees and shoulders, and atophy/rhinitis/eczema, deserve the investigation
of larger cohorts in order to define their relationship with iPPSD4 and iPPSD5 (78).
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PTH resistance should be treated in order to maintain normo-calcemia. Oral calcium supplementation and
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active vitamin D metabolites, preferentially calcitriol or alfa-calcidiol, represent the main therapeutic option.
Being preserved the calcium-reabsorbing action of PTH in the distal nephron, hypercalciuria rarely occurs
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during treatment so that calcium and vitamin D supplementation can be given at doses higher than those
usually used in primary hypoparathyroidism, although caution is still required as for potential side effects at
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the kidney level. To avoid any potential skeletal demineralization effects of PTH excess, it is important to
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normalize calcium levels and lower circulating PTH as much as possible (100). Vitamin D active analogues
may be started during the development of PTH resistance, once PTH rises, to prevent severe hypocalcemia.
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Mostly during infancy and childhood, phosphorus chelants may be necessary to ameliorate
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hyperphosphoremia.
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TSH and gonadotropin resistance should be treated as any other form of hypothyroidism or hypogonadism
Short stature most probably results from a combination of the premature fusion of growth plates, causing the
loss of the puberal growth spurt, and a GH deficiency. A pilot study on rhGH replacement therapy showed
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that height and growth velocity may be improved by the administration during the limited time window of
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the pre-pubertal linear growth, although, actually, no conclusive data are available on the treatment of GH
deficiency (101).
With regard to weight and BMI, patients should counteract the tendency to develop obesity by an appropriate
dietary and exercise intervention. No specific therapies for physical and neurocognitive manifestations are
available. As for heterotopic ossifications, the only opportunity is surgical excision, to be considered just in
6. Conclusions
iPPSDs are heterogeneous but closely related disorders caused by different and complex (epi)genetic defects.
Indeed, patients face a wide range of problems from early childhood to adulthood, including severe
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hypothyroidism, hypogonadism and GH deficiency, growth impairment independently of hormonal status,
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skeletal issues, ectopic ossifications with potential severe limitation in mobility, and cognitive and/or
psychomotor impairment. For these reasons a multidisciplinary approach for getting a correct diagnosis,
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management and follow-up is mandatory, as a specialized expertise is required to manage each of the many
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PRACTICE POINTS
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• PTH resistance is defined by the co-existence of elevated serum levels of PTH, hypocalcemia, elevated
phosphatemia, normal renal function and normal magnesium levels, in the absence of vitamin D
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deficiency.
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• The objectives of conventional management of PTH resistance include maintenance of serum levels of
calcium and phosphorus within the normal range, while avoiding hypercalciuria, and lowering PTH levels
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as permitted.
• The impairment of the Gsα/cAMP/PKA pathway mostly affects the signaling of PTH/PTHrP, and, with
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different severity, the signaling of additional hormones, including TSH, GHRH, calcitonin and
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gonadotropins. These resistances can be detected at different stages of life in the patients, with different
• The diagnosis of TSH resistance is defined by elevated TSH levels, with normal or low free thyroid
hormones levels, usually in the absence of goiter and antithyroid antibodies. It may develop over early
• iPPSD2 is caused by inactivating mutations at the GNAS gene. Mutations at the maternal allele are
associated with PHP1A and PHP1C, which curse with AHO and hormone resistance; when they affect the
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paternal allele, lead to PPHP or POH. PPHP is manifested with AHO without hormone resistance,
whereas POH is characterized by ectopic ossifications rarely associated with AHO features.
• iPPSD3 is characterized by PTH renal resistance, frequently also TSH resistance, in the absence of other
physical abnormalities. This subgroup includes disorders associated with changes in the methylation
pattern of GNAS DMRs, including primary epigenetic defects, UPD(20)pat and deletions of the
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imprinting control region located within STX16 and/or NESP55 DMR.
• iPPSD4 and iPPSD5 refer to ACRDYS1 and ACRDYS2, respectively, which are rare congenital skeletal
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displasias with AHO-like features. About 65% of ACRDYS1 and 15% of ACRDYS2 patients present
with PTH and TSH resistance. iPPSD4 and iPPSD5 derive from autosomal dominant genetic defects,
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affecting different functional domains of PRKAR1A and PDE4D, respectively.
• iPPSDs are heterogeneous but closely related disorders caused by different and complex (epi)genetic
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defects. As patients face a wide range of problems from early childhood to adulthood, specialized and
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multidisciplinary expertise is required to manage each of the many clinical aspects and potential
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complications.
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RESEARCH AGENDA
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While considerable progress has been made over the past years in the genetic diagnosis as well as patients’
managment and follow up, challenges still exist as to the anticipation and prevention of long-term
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complications related to the natural history of these disorders. Thus, future research should focus on:
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• The precise characterization of the natural history study of these disorders by a multicenter, international
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and systematic collection of clinical, biochemical and health-related quality of life data.
• The prevention of long-term complications associated with PTH resistance through the optimization and
• The improvement of final height through the optimization of indications, doses, efficacy and framework
development and progression of ectopic ossifications, with the aim of preventing them and, when present,
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Summary
The non-responsiveness to the PTH/PTHrP pathway derives from molecular alterations affecting different
members of the GPCRs signaling in target organs, including both the PTHR1 receptor and downstream
The complex (epi)genetic defects affecting signalling molecules of the Gsα/cAMP/PKA pathway cause
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different but related diseases, collectively named as inactivating PTH/PTHrP Signaling Disorder (iPPSD)
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(previously Pseudohypoparathyroidism, Pseudopseudohypoparathyroidism, Progressive Osseous
Heteroplasia, Acrodysostosis).
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Patients face a wide range of problems from early childhood to adulthood, including severe alterations of
mineral metabolism, endocrine disturbances due to other hormone resistances, growth impairment
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independently of hormonal status, skeletal issues, ectopic ossifications, and cognitive and/or psychomotor
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impairment.
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Genetic variants of the PTHR1 gene are associated with the iPPSD1 cluster that includes the Blomstrand
chondrodysplasia and the Eiken syndrome, with a recessive transmission pattern of inheritance.
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The iPPSD2 cluster, associated with genetic GNAS defects, comprises Pseudohypoparathyroidism type 1A,
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heteroplasia.
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The iPPSD3 subgroup includes disorders associated with changes in the methylation pattern of GNAS
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DMRs, including primary epigenetic defects and conditions secondary to UPD(20)pat and to deletions of the
AC
iPPSD4 and iPPSD5 derive from autosomal dominant genetic defects affecting PRKAR1A and PDE4D
genes, respectively. iPPSD6 is associated with genetic variants affecting the PDE3A gene.
iPPSDs show a molecular and clinical overlap that makes sometimes challenging and time-consuming to
perform a precise differential diagnosis. A multidisciplinary approach to reach a correct diagnosis together
Acknowledgements: This work was supported by Ricerca Corrente Funds from Fondazione IRCCS Ca’
Granda Policlinico Ospedale Maggiore (to GM); a grant from the Instituto de Salud Carlos III (Institute of
Health Carlos III) of the Ministry of Economy and Competitiveness (Spain) (to GPdN and AP), co-financed
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by the European Regional Development Fund (PI16-00073), a grant from the Department of Health of the
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Basque Government (GV2017/111040 to GPdN). The authors are members of the Euro-
Pseudohypoparathyroidism network (EuroPHP). All members of the EuroPHP network have been members
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of the EUCID.net (COST action BM1208 on imprinting disorders; www.imprinting-disorders.eu).
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Conflict of interest statement: The authors declare no competing interests.
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LEGEND TO THE FIGURE
Figure 1. Schematic representacion of the Gsα/PKA/AMPc signaling pathway. (A) Several hormones
(PTH, PTHrP, TSH, gonadotropin, GHRH, calcitonin, epinephrin) act throught this pathway. (B) The
hormone binding to the G-protein-coupled receptor (GPCR) activates the Gsα subunit by exchanging GDP
with GTP, which is realeased from its heterotrimeric form and (C) travels by the cell membrane to interact
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with the adenylate ciclase (AC), promoting cAMP production. (D) cAMP binds to the regulatory subunits of
the cAMP-dependent PKA enzyme, causing them to break apart from the catalytic subunits and (E) allowing
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its activation and subsequent phosphorylation of transcription factors. The PDE4D convert cAMP into AMP
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to swith off the signal. (F) Phosphorylation of the transcription factors converts them into their active form,
so, after going into the nucleous, they regulate gene expression.
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Table 1: Correlation between the novel and classical classifications for PTH/PTHrP signaling disorders
Novel
Classical classification OMIM Phenotype Molecular determinant
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classification
BLOMSTRAND
# 215045 skeletal dysplasia, advanced skeletal maturation, lethal
CHONDRODYSPLASIA PTHR1 mutations (AR, BOCD: LoF [PMID: 17164305]; Eiken: GoF [PMID:
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iPPSD1
7721741])
EIKEN SYNDROME # 600002 skeletal dysplasia, severely delayed skeletal maturation
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# 103580 Multihormonal resistance, AHO
PHP1A Maternal LoF point mutation/deletion GNAS [PMID: 2109828]
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# 612462
PHP1C Maternal LoF point mutation GNAS exon 13; LoI at GNAS DMRs
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(few cases reported)
iPPSD2 AHO
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PPHP Paternal LoF point mutation/deletion GNAS
# 612463
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POH
# 166350 Heterotopic ossification
Paternal LoF point mutation/deletion GNAS
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Sporadic: LoI at GNAS DMRs; UPD(20)pat
iPPSD3 PHP1B # 603233 Multihormonal resistance (rarely signs of AHO) Familial (AD): isolated LoM at GNAS A/B:TSS-DMR (maternal STX16
deletion); LoI at GNAS DMRs(maternal NESP and/or AS deletion)
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iPPSD4 ACRDYS1 # 101800 skeletal dysplasia, AHO-like, multiple endocrine abnormalities PRKAR1A mutations (GoF of the subunit, LoF of PKA [PMID: 21651393])
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iPPSD5 ACRDYS2 # 614613 skeletal dysplasia, AHO-like, intellectual disability PDE4D mutations (GoF) [PMID: 14602083]
AR: autosomal recessive; LoF: loss of function; GoF: gain of function; LoI: loss of imprinting; LoM: loss of methylation; AD: autosomal dominant.
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