Abnormal Parathyroid Hormone Receptor Signaling

DERANGED CALCIOTROPIC HORMONAL ACTIVITY

Pseudohypoparathyroidism Ia (PHP1A, OMIM phenotype number #103580)
Pseudohypoparathyroidism Ib (PHP1B, OMIM phenotype number #603233)
Pseudohypoparathyroidism Ic (PHP1C, OMIM phenotype number #612462)
Pseudohypoparathyroidism II (PHP2, OMIM phenotype number #203330)
Pseudopseudohypoparathyroidism (PPHP, OMIM phenotype number #240300)

The term pseudohypoparathyroidism encompasses several rare related metabolic disorders characterized by features of functional hypoparathyroidism (hypocalcemia, hyperphosphatemia) but with high serum PTH levels.
Pseudohypoparathyroidism Ia (PHP1A, OMIM phenotype number #103580) is caused by maternally inherited mutations in G protein subunit alpha (Gs alpha, OMIM gene number #139320, on chromosome 20q13.32), a protein essential for transmembrane hormone receptor signaling and differentially expressed in different tissues because of genetic imprinting. Genetic imprinting is an epigenetic phenomenon by which some genes are expressed in a parent-of-origin specific manner. In the kidney and other endocrine glands the maternal copy of the gene is expressed, so that when mutations in Gs alpha are inherited from the mother will determine the features of PhP1A. PHP1A can be sporadic or inherited as a autosomal dominant trait. Along with hypoparathyroidism, which is not generally present at birth but manifest later usually in the first decade, characterized by hypocalcemia and hyperphosphatemia, with inappropriately high PTH levels, other somatic developmental abnormalities are characteristics of the disease, resulting in the so called Albright ereditary osteodistrophy (AHO). Individuals with AHO with central obesity, short stature, rounded face with short and low-set nasal bridge, short neck, brachydactyly with shortening of one or more metacarpals or metatarsals, and various degrees of mental retardation. Sometimes, ectopic ossification of subcutaneous tissues can be present. As a distinctive feature, PTH stimulus fails to increase urinary PTH, demonstrating renal resistance to the action of PTH due to altered maternally inherited Gs alpha in the kidney. In affected individual, resistance to multiple peptide hormones acting via Gs alpha signaling through G-protein coupled receptors, such as TSH, ACTH, gonadotropins, growth hormone releasing hormone (GHRH). When the Gs alpha mutation is paternally inherited, since the paternal allele is inactivated in the kidney, AHO is present without hypoparathyroidism, configuring pseudopseudohypoparathyroidism (PPHP, OMIM phenotype number #240300). Subjects with PPHP often carry ectopic bone in the dermis or subcutaneous fat. Progressive osseous heteroplasia (POH, OMIM phenotype number #166350), consists of a dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. It is caused by paternally inherited GS alpha mutations.
Usually, cases of PHP1A and PPHP coexist in the same family, depending on whether the mutation is inherited from the mother or the father, respectively. Pseudohypoparathyroidism type Ic (PHP1c, OMIM phenotype number #612462) is clinically indistinguishable for PHP1A, but with preserved Gs alpha activity in blood cells in vitro. Some of these patients harbor a mutation in Gs alpha which impairs the interaction with the hormone receptor but it does not affect cAMP production.
Pseudohypoparathyroidism Ib (PHP1B, OMIM phenotype number #603233) is a disorder due to epigenetic alterations (i.e. altered methylation) in Gs alpha locus (GNAS) leading to altered imprinting of the gene and lack of the expression of maternal allele in renal tissue. In some cases isolated renal resistance to PTH without the features of Albright hereditary osteodystrophy characterizes the disease. Most cases are sporadic, while few cases are familial. In familial cases STX16 mutations affecting GNAS imprinting have been demonstrated. Few patients present various degrees of bone involvement from mild bone loss and osteoporosis, to severe forms of osteitis fibrosa cystica characterized by markedly elevated bone resorption leading to cyst-like brown tumors throughout the skeleton, because of the detrimental effects of markedly elevated PTH on bone.

Genes

In PHP1A, PHP1C and PPHP inactivating mutations of Gs alpha (OMIM gene number #139320, on chromosome 20q13.32); in PHP1B altered methylation of GNAs locus, in some cases gene deletions

Phenotype

Increased neuromuscular irritability (spasms, tetany, seizures) ocular (cataracts), cardiovascular (prolongation QT interval), soft tissue calcifications; features of AHO in PHP1A, PHP1C and PPHP. Osteitis fibrosa cystica in some cases of PHP1B.

Main biochemical alterations:

PHP1A low Ca, high Pi, high PTH levels in the absence of vitamin D deficiency, low/normal 1-25(OH)2D3, associated with low Ur cAMP in response to PTH infusion and multiple hormone resistance (e.g. blunted GH response to provocative tests, high LH and FSH with low estradiol and testosterone levels, high TSH levels without thyroid autoantibodies and normal thyroid scan)
PHP1B low Ca, high Pi, high PTH levels in the absence of vitamin D deficiency, low/normal 1-25(OH)2D3, associated with low Ur cAMP in response to PTH infusion; multiple hormone resistance syndromes may be present.

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Acrodysostosis 1 (ACRDYS1)

Acrodysostosis comprises a heterogeneous group of rare skeletal dysplasia that share characteristic features, such as severe brachydactyly, facial dysostosis and nasal hypoplasia.

(OMIM phenotype number #101800)

Acrodysostosis comprises a heterogeneous group of rare skeletal dysplasia that share characteristic features, such as severe brachydactyly, facial dysostosis and nasal hypoplasia. Moreover, various degrees of intellectual disability and/or behavioral disorders have also been described in patients affected by Acrodysostosis. This disease include two types caused by two distinct genes, those coding for the type 1 regulatory subunit of cAMP-dependent protein kinase alpha (PRKAR1A) or the cAMP-specific phospho-diesterase 4D (PDE4D). Both of these proteins are important components in the (G-protein-coupled receptors) GPCR-Gsa-cAMP-protein kinase A signaling pathway. These mutations have a different impact in different tissues, explaining the phenotypic heterogeneity, in particular the presence or absence of hormonal resistance. Currently, less than 80 cases have been reported in the literature to date. ACRDYS1 is caused by heterozygous mutation in the PRKAR1A gene and is characterized by short stature, severe brachydactyly, facial dysostosis, nasal hypoplasia, advanced bone age, obesity and multiple hormone resistance.

Diagnosis is based on the clinical, biochemical and radiological characteristics. Differential diagnosis includes: brachydactyly type E, pseudohypoparathyroidism 1a or pseudopseudohypoparathyroidism.

Treatment: No specific treatment for acrodysostosis exist, up to date. Nevertheless, hormonal resistances, in particular to PTH and TSH, can be treated appropriately as in any other form of hypoparathyroidism and hypothyroidism. At last, dietary and lifestyle measures are recommended to prevent obesity.

Gene

PRKAR1A gene, 17q24.2 (OMIM gene/locus number #188830).

Phenotype

Form of skeletal dysplasia characterized by brachydactyly, short stature, obesity, facial dysostosis (broad face, widely spaced eyes, maxillo-nasal hypoplasia), small broad hands and feet with stubby digits, except for the big toe, which is enlarged.

Main biochemical alterations

Low or normal Ca and Pi, low or normal PTH, ± multiple hormone resistance.

Images

Fig. Photographs and X rays of the face and hand of a 12-year-old patient affected with ACRDYS1 resulting from the R368X mutation in PRKAR1A. (a) Side and (b) front photographs of the face. Note the facial dysostosis and severe maxilla-nasal hypoplasia. Photograph (c) and radiograph (d) of the left hand. Note the shortening of all metacarpals and phalanges, and the bulky and stocky aspect of all the affected bones. Standard X-rays show the short and broad metacarpals and phalanges, the cone-shaped epiphyses and advanced carpal and tarsal maturation.

Acrodysostosis 2 (ACRDYS2)

(OMIM phenotype number #614613)

Acrodysostosis is a rare skeletal dysplasia, which includes two forms, Acrodysostosis 1 (ACRDYS1) and ACRDYS2, with similar clinical characteristics, such as severe brachydactyly, facial dysostosis and nasal hypoplasia, and different mutations (see also ACRDYS1). ACRDYS2 is caused by heterozygous mutation in the PDE4D gene, encoding cAMP-specific phospho-diesterase 4D. This disease is characterized by brachydactyly, facial dysostosis, spinal stenosis, short stature, often intellectual disability and in some rare cases hormone resistance. The maxillo-nasal hypoplasia with flattening of nasal ridge appears to be more severe in ACRDYS2 patients, and some patients with do not present a short stature than ACRDYS1. See also ACRDYS1.

Gene

PDE4D gene, 5q12 (OMIM gene/locus number #600129).

Phenotype

Main biochemical alterations

Low or normal Ca and Pi, low or normal PTH, ± multiple hormone resistance (rare).

Progressive osseous heteroplasia (POH)

(OMIM phenotype number #166350)

Progressive osseous heteroplasia (POH) is a very rare genetic disease characterized by progressive ectopic ossification. This disease is generally caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene on the paternal allele. GNAS gene encodes the alpha subunit of the G-stimulatory protein of adenylyl cyclase. Cutaneous ossification usually presents in early life, and involves subcutaneous and then subsequently deep connective tissues (muscle and fascia). Other diseases, such as Albright hereditary dystrophy, pseudohypoparathyroidism, and primary osteoma cutis are caused by inactivating mutations of GNAS, and share common features of superficial heterotopic ossification. POH is distinguished clinically from these other related diseases by the deep and progressive nature of the heterotopic bone. The degree of morbidity depends on the location and extent of heterotopic ossification, resulting, in some cases, in severe disability. Few data exist about prognosis.

Treatment: Currently, there are no effective treatments or prevention for POH. Surgical resection of diffuse lesions usually leads to recurrences or complications, but in some cases, areas of circumscribed heterotopic ossification can be removed by surgery, with successful long-term outcomes.

Gene

GNAS (paternal) gene, 20q13.32 (OMIM gene/locus number *139320).

Phenotype

Heterotopic ossifications in the dermis (osteoma cutis) with possible extension to deep tissues, intramembranous ossification, and growth retardation of affected limbs due to heterotopic bone formation.

Main biochemical alterations

Normal Ca, normal Pi, normal PTH.

Images

Fig. Appearance of heterotopic ossification in POH. (a-b) Early clinical appearance of heterotopic ossification in POH. Note the maculopapular lesions that correspond to extensive dermal and subcutaneous ossification.

Reproduced from Appl Clin Genet. 2015 Jan 30;8:37-48 under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) License.

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McCune-Albright syndrome (MAS)

McCune-Albright syndrome (MAS) is rare disease caused by an early embryonic postzygotic somatic activating mutations in the GNAS1 gene, encoding the cAMP pathway-associated G-protein, Gsα.

(OMIM phenotype number #174800)

McCune-Albright syndrome (MAS) is rare disease caused by an early embryonic postzygotic somatic activating mutations in the GNAS1 gene, encoding the cAMP pathway-associated G-protein, Gsα. The estimated prevalence is between 1/100.000 and 1/1.000.000. MAS is classically defined by the triad of fibrous dysplasia (FD), hyperpigmented (café-au-lait) skin lesions, and gonadotropin-independent sexual precocity. Moreover, MAS can include other endocrinopathies, such as hyperthyroidism, growth hormone excess, renal phosphate wasting with or without rickets/osteomalacia and Cushing syndrome. Rarely, other organ systems may be involved (i.e. liver, cardiac, parathyroid, and pancreas).

Diagnosis of MAS is based on the finding of two or more typical clinical features. The prognosis of the disease is based on lesions location and severity. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS. Differential diagnoses include: neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm.

Treatment is based on the tissues affected. The therapeutic management include: surgical intervention, the use of bisphosphonates and strengthening exercises for FD. Treatment of all endocrinopathies is required.

Gene

GNAS gene, 20q13.32 (OMIM gene/locus number *139320)

Phenotype

Disorder that affects the bones, skin (café-au-lait pigmentation), and several endocrine tissues with possible precocious puberty, hyperthyroidism, excessive secretion of growth hormone,
Cushing syndrome, hyperparathyroidism, acromegaly, hyperprolactinemia, polyostotic fibrous dysplasia (scar-like/fibrous tissue in the bones, often confined to one side of the body), some cases of hypophosphatemic osteomalacia, and craniofacial hyperostosis.

Main biochemical alterations:

Normal-high Ca, normal-low Pi, normal-high PTH, normal/high 1-25(OH)2D3 + other endocrine abnormalities.

Images

Fig. 1) Café-au-lait skin pigmentation. (a) Skin lesions in a newborn demonstrating the characteristic association with the midline of the body, and distribution reflecting patterns of embryonic cell migration (developmental lines of Blaschko). (b) A typical lesion on the chest, face, and arm demostrating the irregular "coast of Maine" borders, relationship with the midline of the body, and distribution following developmental lines of Blaschko. (c). Typical lesions frequently found on the nape of the neck and crease of the buttocks.

Fig. 2) (a) Proximal femur FD demonstrating the typical ground glass appearance with a coxa vara (“shepherd’s crook”) deformity. (b) Three-dimensional reconstructed computed tomography (CT) image of a man age 26 years with craniofacial FD and uncontrolled growth hormone excess, leading to macrocephaly and severe facial deformity.

Reproduced with permission and copyright © 1993-2015 of the University of Washington, Seattle. Boyce AM and Collins MT, Fibrous Dysplasia/McCune-Albright Syndrome http://www.ncbi.nlm.nih.gov/books/NBK274564/. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® www.ncbi.nlm.nih.gov/books/NBK1116/.

Metaphyseal chondrodysplasia Jansen type (JMC)

Metaphyseal chondrodysplasia Jansen type (JMC) is a rare autosomal dominant skeletal disease caused by mutations in the PTH/PTHrP receptor (PTH1R) gene.

(OMIM phenotype number #156400)

Metaphyseal chondrodysplasia Jansen type (JMC) is a rare autosomal dominant skeletal disease caused by mutations in the PTH/PTHrP receptor (PTH1R) gene. The mutation leads to constitutive activation of the receptor independent of PTH or PTHrP. JMC is usually characterized by short stature, bowed legs, waddling gait, contracture deformities of the joints, and short hands with clubbed fingers. Until now, four distinct mutations in PTH1R have been described in patients affected by JMC. Three of these mutations were identified in the classic form of the disease (p.His223Arg, p.Thr410Pro, p.Ile458Arg) while the fourth one (p.Thr410Arg) appears to be associated with less pronounced skeletal and laboratory abnormalities. A nearlier diagnosis is often driven by presence of complications in the neonatal period (i.e. respiratory distress or difficulty in feeding).

Gene

PTHR1 gene, 3p21.31 (OMIM gene/locus number #168468). Chondrodysplasias with mineral ion homeostasis are abnormalities due to alterations of the PTHR1 gene, which usually mediates the actions of the two ligands: PTH and PTH-related peptide. PTHR1 activates several signal transduction pathways, including adenyl cyclase (AC)/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC). (see also BOCD)

Phenotype

High skull vault, flattening of the nose and forehead, low-set ears, hypertelorism, high arched palate, micrognathia, retrognathia, kyphoscoliosis with bell-shaped thorax and widened costochondral junctions, metaphyseal enlargement of the joints, frontonasal hyperplasia, short legs and relatively long arms; in younger patients: enlargement of metaphyses with a wide zone of irregular calcifications (lesions similar to rickets). At puberty: partially calcified cartilage that protrude into diaphysis. Late adolescence: cartilaginous tissue in the metaphysis disappears, sclerosis and thickening of the base of skull with cranial auditory and optical nerve compression.

Main biochemical alterations

High Ca, low Pi, high Ur Pi, high Ur Ca, high Ur cAMP, suppressed/low-normal PTH.

Eiken familial skeletal dysplasia

(OMIM phenotype number #600002)

Eiken syndrome is a rare familial skeletal dysplasia, caused by homozygous mutation in the PTH/PTHrP receptor (PTHR1) gene. This disease is characterized by multiple epiphyseal dysplasia, with extremely retarded ossification (principally of the epiphyses, pelvis, hands and feet), as well as by abnormal modeling of the bones in hands and feet, abnormal persistence of cartilage in the pelvis and mild growth retardation. It has been described in a unique consanguineous family and the transmission is autosomal recessive. Eiken familial skeletal dysplasia and Blomstrand chondrodysplasia (see also BOCD) are both caused by recessive mutations in PTHR1, but patients with Eiken syndrome have a severely delayed skeletal maturation. The phenotype in Eiken syndrome is more similar to Jansen chondrodysplasia (see also JMC), although the syndromes clearly differ by the mode of inheritance, specific skeletal features and calcium (Ca) and phosphate (Pi) concentrations.

Gene

Phenotype

Multiple epiphyseal dysplasia, severely retarded ossification of epiphyses, pelvis, hands, and feet, abnormal modeling of bones of hands and feet. No mental retardation.

Main biochemical alterations

Normal-high PTH, normal Ca, Pi, and 1,25(OH)2D.

Multiple enchondromatosis, Ollier type

(OMIM phenotype number %166000)

Enchondromatosis is a rare heterogeneous skeletal disease characterized by multiple enchondromas, and it includes several different subtypes of which Ollier disease and Maffucci syndrome are most common. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. Ollier disease (also known as dyschondroplasia, multiple cartilaginous enchondromatosis, en- chondromatosis Spranger type I) is characterized by multiple enchondromatosis with an asymmetric distribution. Lesions are usually distributed in the appendicular skeleton (the skull and vertebral bodies are very rarely involved). In particular, enchondromas are most commonly seen in phalanges and metacarpals and rarely in the carpal bones. However, there is a wide variety of presentations in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, and requirement for surgery. Clinical problems caused by enchondromas include skeletal deformities, limb-length discrepancy, and the potential risk for malignant change to chondrosarcoma. Malignant transformation of one or more enchondromas towards secondary central chondrosarcoma is estimated to occur in 5-50% of the patients. Radiologically, Ollier disease presents with asymmetrical osteolytic lesions with well-defined, sclerotic margins. Clinical manifestations of Ollier disease often manifests itself in the first decade of life without any significant gender bias, but has also been reported in early adolescence and adulthood. The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome. The estimated prevalence of Ollier disease is 1/100.000. The pathogenesis of enchondromatosis is not clearly understood. Recently, heterozygous mutations of PTHR1, IDH1 (most common), and/or IDH2 genes have been suggested as genetic aberrations. The inheritance pattern of Ollier disease is unknown but is thought to not be simply a Mendelian pattern. The diagnosis is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. Ollier disease must be differentiated from multiple hereditary exostosis, and radiologically, Ollier disease may mimic osteitis fibrosa cystica.

There is no medical treatment for enchondromatosis, but treatment of Ollier disease is usually conservative. Surgery is performed in cases of complications and malignant transformation.

Gene

PTHR1 gene, 3p21.31 (OMIM gene/locus number *168468); IDH1 gene, 2q34 (OMIM gene/locus number *147700); IDH2 gene, 15q26.1 (OMIM gene/locus number *147650).

Phenotype

Soft tissue hemangiomas (Maffucci syndrome), multiple enchondromas with skeletal deformities and potential risk for malignant change to chondrosarcoma.

Main biochemical alterations

Slightly high PTH.

Images

Fig. (a) 4-year-old female patient with Ollier disease. Multiple enchondromas, manifesting as central end eccentric osteolytic lesions and deformities in the metacarpals and phalanges of the fourth and fifth ray of the right hand. (b) Same patient 13 years later. The enchondromas have increased in size and some are more evidently visible compared to the previous study. This has resulted in deformity of the fourth finger.

Reproduced from Pansuriya TC, Kroon HM, Bovée JV, Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol 2010;3:557-69.

Chondrodysplasia Blomstrand type (BOCD)

(OMIM phenotype number #215045)

Chondrodysplasia Blomstrand type (BOCD) is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous inactivating mutations in the parathyroid hormone receptor-1 gene. The estimated prevalence is <1/1.000.000. Until now, few cases have been reported in the literature. The disease is characterized by multiple malformations, very short limbs and dwarfism, a narrow thorax, facial anomalies (macroglossia, micrognathia, and depressed nasal bridge), polyhydramnios, hydrops fetalis, hypoplastic lungs, protruding eyes showing cataracts, and internal malformations such as preductal aortic coarctation. It has been described increased bone mineral density and advanced bone maturation in the fetues. Signs of the disease are present at birth, and it leads to neonatal death.

Gene

PTHR1 gene, 3p21.31 (OMIM gene/locus number #168468).
Chondrodysplasias with mineral ion homeostasis are abnormalities due to alterations of the PTH/PTHrP receptor gene (PTHR1) gene, which usually mediates the actions of the two ligands: PTH and PTH-related peptide. The PTH1R is a member of the G protein-coupled receptor family 2, and its activity is mediated by G proteins that activate adenylate (AC)/protein kinase A (PKA) and the phospholipase C beta (PLCβ)/protein kinase C (PKC) signaling pathway. The PTH receptor is expressed in most tissues but with particularly high levels in bone, kidneys, and growth plate. Recently it has been shown that signaling through the PTH/PTHrP receptor, in addition to its role in regulating mineral metabolism, has an important role in fetal development due to the regulatory effects of PTHrP on the development of cartilage and bone.

Phenotype

Early lethality, defects of mammary gland and of tooth development, hypoplasia of nasal, mandibular and facial bones, short thick ribs, hypoplasia of the vertebrae, hyperdensity of the whole skeleton, markedly advanced ossification. Long bones: extremely short and poorly modeled, no zones of chondrocyte proliferation and of column formation are lacking.

Main biochemical alterations

Low Ca, high PTH, low Ur Pi, high Ur cAMP.

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