Albright Hereditary Research Articles

Albright's Hereditary Osteodystrophy: A Rare Genetic Disorder Diagnosed on Standard Radiography.

Teaching point: Some genetic syndromes have characteristic features that allow for their diagnosis to be made based on radiological findings.

Prevalence Allusions of Albright’s Hereditary Osteodystrophy Syndrome in South Asia

Albright's Hereditary Osteodystrophy (AHO) is a rare, complex genetic metabolic disorder that was first delineated by American endocrinologist Fuller Albright in 1942. This syndrome is characterized by physical features such as short stature, abnormal finger and toe bones, skin ossification, obesity, rounded facial appearance, flat nasal bridge, and in some cases, developmental and mental abnormalities. AHO is classified as a subtype of pseudohypoparathyroidism type 1A due to its association with resistance to parathyroid hormone. When AHO is inherited from parents, it leads to the development of the syndrome without hormonal issues, resulting in a condition known as Pseudo-Pseudo Hypoparathyroidism (PPHP). PPHP is inherited in an autosomal dominant manner, caused by a mutation in the GNAS gene. This gene is responsible for producing a subunit of a protein called a G protein, which regulates the activity and production of specific hormones, including parathyroid hormone. Globally, AHO is considered a rare syndrome, with a prevalence of 0.7 in 100 individuals. It is further classified into subtypes 1a, 1b, 1c, and 2 based on different phenotypes and underlying mechanisms. However, the purpose of this study is to investigate the rarity of the syndrome in the Asian subcontinent, specifically examining its prevalence, recent trends, and awareness within the selected demographic population. A survey-based approach was employed to gather data from several Asian countries. The findings of this study revealed significant variations in terms of gender distribution, family history, associated complications, Gs alpha subunit deficiency, and the age at which individuals are diagnosed with the syndrome. These variations underscore the need for a versatile approach to accurately diagnose and promptly treat individuals at risk of or already affected by the syndrome.

PSAT185 Pseudohypoparathyroidism Type 1B: A Medication Compliance Challenge

Abstract Introduction Pseudohypoparathyroidism (PHP) encompasses five metabolic disorders characterized by target organ PTH resistance. The focus of this paper is PHP Type 1B (PHP1B), a disease that typically presents in children with symptomatic hypocalcemia. Only 15-20% of cases are genetic, making our case of Familial PHP1B even rarer. Case Presentation A 23-year-old African-American female with hypothyroidism and PHP1B diagnosed in 2005 presented to the emergency department with symptomatic hypocalcemia. As a child, she was evaluated for progressive femur, tibia, radius, and ulna bowing in the setting of short stature without phenotypic features of Albright's Hereditary Osteodystrophy. Her biochemical profile was consistent with pseudohypoparathyroidism and imaging showed costochondral junction enlargement. Genetic testing revealed STX mutation confirming PHP1B diagnosis. Extensive studies of her family revealed several affected members, including one of her two children.Patient has history of multiple hospitalizations for symptomatic hypocalcemia. During this admission, her laboratories demonstrated: calcium 4.4 mg/dL (8.6-10.3 mg/dL), phosphorus 7.3 mg/dL (2.5-4.5 mg/dL), PTH 574 pg/mL (16-65 pg/mL), 1,25-dihyroxyvitamin D < 8 ng/mL (18-78 ng/mL), and 25-hydroxyvitamin D 7.6 ng/mL (30-100 ng/mL).She has an extensive history of non-compliance with medications and endocrinology appointments. During the last visit, she complained of ostealgia, particularly in long bones. While discussing the importance of maintaining adequate calcium levels, the patient expressed feeling overwhelmed by her regimen (calcitriol 1 mcg QAM and 0.5 mcg QHS, calcium carbonate 1,200 mg TID). After a lengthy conversation regarding the need for long-term medical therapy, she became increasingly distraught. Conclusion When normocalcemia is achieved with high doses of calcium and calcitriol, patients with PHP1B have an average life expectancy. Given that patients are typically diagnosed in childhood, taking several medications multiple times a day can be challenging and lead to poor compliance. When this occurs, PHP1B becomes a life-altering disease with a significant decrease in quality of life.In 2018 Wierenga et al. reported that being emotionally overwhelmed by chronic disease prevents a patient from appropriately caring for themselves. Their research shows that older males with higher levels of education have better emotional regulation than young females with low educational levels. Providing patients at high risk of psychological stress with a multidisciplinary team including cognitive-behavioral therapists can improve their quality of life and compliance while decreasing the healthcare costs associated with poorly controlled chronic diseases. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause.

The PTH/PTHrP receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) by coupling this G protein-coupled receptor (GPCR) to the alpha-subunit of the heterotrimeric stimulatory G protein (Gsα) and thereby to the formation of cAMP. In growth plates, PTHrP-dependent activation of the cAMP/PKA second messenger pathway prevents the premature differentiation of chondrocytes into hypertrophic cells resulting in delayed growth plate closure. Heterozygous mutations in GNAS, the gene encoding Gsα, lead to a reduction in cAMP levels in growth plate chondrocytes that is sufficient to cause shortening of metacarpals and/or -tarsals, i. e. typical skeletal aspects of Albright's Hereditary Osteodystrophy (AHO). However, heterozygous mutations in other genes, including those encoding PTHrP, PRKAR1A, PDE4D, and PDE3A, can lead to similar or even more pronounced acceleration of skeletal maturation that is particularly obvious in hands and feet, and reduces final adult height. Genetic mutations other than those resulting in Gsα haploinsufficiency thus reduce intracellular cAMP levels in growth plate chondrocytes to a similar extent and thereby accelerate skeletal maturation.

Albright's Hereditary Osteodystrophy associated with resistance to insulin and thyroid hormone in three male siblings

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Manifestation of hormone resistance depends on the type of inheritance in Albright's Hereditary Osteodystrophy

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B

GNAS exons 1–13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Gαs). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Gαs exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Gαs expression through loss-of-methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1–13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1 was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B.

Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.

BackgroundGenetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright’s Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing.In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders.MethodsThe molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards.ResultsIn patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded.ConclusionsA dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.

A Novel T55A Variant of Gs α Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis.

G-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities. The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations classically lead to Albright's Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism. We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH. Exome sequencing revealed a novel de novo heterozygous missense mutation of GNAS (c.163A<G, p.T55A) affecting the p-loop of the catalytic Gsα GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of Gsα, we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation. We identified a 64% decrease in isoproterenol-induced cAMP production in vitro, compared to wild type, consistent with loss of Gsα activity. Despite a significant decrease in isoproterenol-induced cAMP production in vitro, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis.

Progress of diagnosis and clinical management of pseudohypoparathyroidism

Pseudohypoparathyroidism(PHP) is a rare genetic disorder.The main character is parathyroid hormone resistance, and some with typical Albright's Hereditary Osteodystrothy malformation.The wide range of PHP symptom spectrum may lead to miss or misdiagnosis.This paper reviewed and summarized the pathogenesis, manifestation and the progress on the diagnosis and treatment of PHPⅠ, so as to improve the diagnostic level of this disease. Key words: Pseudohypoparathyroidism; Albright's hereditary osteodystrothy; Hypocalcemia; GNAS1 gene; Diagnosis; Treatment

Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)

Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q13.3 encoding Gsα and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6±1.45years. Calcium, phosphate, and PTH were 6.3±0.23mg/dL, 7.7±0.33mg/dL, and 305±34.5pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians.

Different Biochemical Properties Explain Why Two Equivalent Gα Subunit Mutants Cause Unrelated Diseases

There is an increasing number of disease-associated Gα mutations identified from genome-wide sequencing campaigns or targeted efforts. Albright's Hereditary Osteodystrophy (AHO) was the first inherited disease associated with loss-of-function mutations in a G protein (Gαs) and other studies revealed gain-of-function Gα mutations in cancer. Here we attempted to solve the apparent quandary posed by the fact that the same mutation in two different G proteins appeared associated with both AHO and cancer. We first confirmed the presence of an inherited Gαs-R265H mutation from a previously described clinical case report of AHO. This mutation is structurally analogous to Gαo-R243H, an oncogenic mutant with increased activity in vitro and in cells due to rapid nucleotide exchange. We found that, contrary to Gαo-R243H, Gαs-R265H activity is compromised due to greatly impaired nucleotide binding in vitro and in cells. We obtained equivalent results when comparing another AHO mutation in Gαs (D173N) with a counterpart cancer mutation in Gαo (D151N). Gαo-R243H binds nucleotides efficiently under steady-state conditions but releases GDP much faster than the WT protein, suggesting diminished affinity for the nucleotide. These results indicate that the same disease-linked mutation in two different G proteins affects a common biochemical feature (nucleotide affinity) but to a different grade depending on the G protein (mild decrease for Gαo and severe for Gαs). We conclude that Gαs-R265H has dramatically impaired nucleotide affinity leading to the loss-of-function in AHO whereas Gαo-R243H has a mild decrease in nucleotide affinity that causes rapid nucleotide turnover and subsequent hyperactivity in cancer.

Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

BackgroundPseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene. PHP-Ib patients have isolated Parathormone (PTH) resistance and GNAS epigenetic defects while PHP-Ia cases present with hormone resistance and characteristic features jointly termed as Albright's Hereditary Osteodystrophy (AHO) due to maternally inherited GNAS mutations or similar epigenetic defects as found for PHP-Ib. Pseudopseudohypoparathyroidism (PPHP) patients with an AHO phenotype and no hormone resistance and progressive osseous heteroplasia (POH) cases have inactivating paternally inherited GNAS mutations.Methodology/Principal FindingsWe here describe 17 subjects with an AHO-like phenotype that could be compatible with having PPHP but none of them carried Gsalpha mutations. Functional platelet studies however showed an obvious Gs hypofunction in the 13 patients that were available for testing. Methylation for the three differentially methylated GNAS regions was quantified via the Sequenom EpiTYPER. Patients showed significant hypermethylation of the XL amplicon compared to controls (36±3 vs. 29±3%; p<0.001); a pattern that is reversed to XL hypomethylation found in PHPIb. Interestingly, XL hypermethylation was associated with reduced XLalphaS protein levels in the patients' platelets. Methylation for NESP and ExonA/B was significantly different for some but not all patients, though most patients have site-specific CpG methylation abnormalities in these amplicons. Since some AHO features are present in other imprinting disorders, the methylation of IGF2, H19, SNURF and GRB10 was quantified. Surprisingly, significant IGF2 hypermethylation (20±10 vs. 14±7%; p<0.05) and SNURF hypomethylation (23±6 vs. 32±6%; p<0.001) was found in patients vs. controls, while H19 and GRB10 methylation was normal.Conclusion/SignificanceIn conclusion, this is the first report of methylation defects including GNAS in patients with an AHO-like phenotype without endocrinological abnormalities. Additional studies are still needed to correlate the methylation defect with the clinical phenotype.

A Novel GNAS1 Mutation in a German Family with Albright's Hereditary Osteodystrophy

Albright's hereditary osteodystrophy (AHO) is an inherited disorder and results from heterozygous loss of function mutation within the human G (s)α gene (GNAS1). AHO appears in two phenotypes, that may occur within the same family. Pseudohypoparathyroidism type Ia (PHP Ia) comprises the clinical features of AHO associated with parathyroid hormone (PTH) resistance while pseudo-pseudohypoparathyroidism (PPHP) includes AHO features without PTH resistance. In the present study we report a mother and a daughter with PPHP and PHP Ia respectively. The 13 exons of GNAS1 were analysed by PCR and direct sequencing. We identified a heterozygous missense mutation in exon 1. This novel mutation results in a stop at codon 35 and a truncated non-functional GNAS1 protein.

A Case of Pseudohypoparathyroidism without Albright's Hereditary Osteodystrophy in an Adult

Pseudohypoparathyroidism is a rare disease caused by resistance to parathyroid hormone, and is associated with typical clinical typical symptoms such as tetany and seizures, hypocalcemia, hyperphosphatemia and increased parathyroid hormone levels. Pseudohypoparathyroidism is classified to Type Ia, Ib, Ic and II according to the clinical and biochemical manifestations. Type Ia and Ic have morphological characteristics called Albright's hereditary osteodystrophy. Type Ib differs from type II for the pathogenesis. Type Ib mayreceptors and type II maypathway, but the pathophysiology of type II is not clear yet. Administration of parathyroid hormone extract may help to distinguish between the two types. We report a case of a pseudohypoparathyroidism type Ib or II patient who had tetany, hypocalcemia and hyperphosphatemia with normal morphologic features.

Determination of Gsα a Protein Activity in Albright's Hereditary Osteodystrophy

Albright's hereditary osteodystrophy (AHO) is a heterogeneous clinical entity in part associated with pseudohypoparathyroidism (PHP) and other endocrinopathies. It may be caused by diminished Gs alpha protein activity. Heterozygous mutations in the underlying GNAS gene on chromosome 20 have been described. One hundred and six patients with suspected AHO, were investigated, of whom 93 showed a laboratory profile of PHP with low or normal calcium and elevated parathormone with normal vitamin D metabolites, and 13 had no endocrine abnormalities. Gs alpha activity was determined in isolated erythrocyte membranes. Molecular genetic analysis of GNAS exons 2-13 was initiated. Significantly reduced Gs alpha activity was found in 91 patients. In 53 patients with reduced Gs alpha activity, a mutation within GNAS was demonstrated. The mutation detection rate was much lower in AHO patients without endocrinopathies than in those who had PHP. In addition, three of the 15 patients with AHO features but normal Gs alpha activity had genetic variations of GNAS. We conclude that determination of Gs alpha activity can be used as a diagnostic screening procedure in patients with suspected AHO. However, the mutation detection rate in GNAS is highly variable. The genetic heterogeneity of AHO needs further investigation.

Effective monosomy or trisomy of chromosome band 2q37.3 due to the unbalanced segregation of a 2;11 translocation.

We report a seven generation family in which a 2;11 chromosome translocation is segregating. Both unbalanced segregants have been found in the family, and cytogenetic analysis demonstrates that this results in effective monosomy or trisomy for chromosome band 2q37.3. Those family members who are monosomic exhibit a variable phenotype with a number of features associated with an Albright's Hereditary Osteodystrophy-like phenotype (AHO-like) whilst those who are trisomic have a phenotypic spectrum ranging from mild facial anomalies and growth retardation to apparent normality. The latter group of patients represent the first reported patients with pure trisomy for chromosome band 2q37.3.

Albright's hereditary osteodystrophy and pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO) are not interchangeable terms. AHO describes a constellation of physical features, including short adult stature, obesity, brachydactyly, and ectopic ossifications. PHP means end-organ resistance to PTH and is subclassified into types Ia, Ib, and Ic and type II. Pseudopseudohypoparathyroidism (PPHP) is a term used for individuals with AHO who have normal end-organ responses to PTH. Both the PHPIa and PPHP forms of AHO result from heterozygous deactivating mutations in the GNAS1 gene associated with a 50% reduction in bioactivity of the Gsalpha protein that it encodes. The GNAS1 gene is subject to tissue-specific genomic imprinting. Patients with mutations on their maternally derived allele are likely to have associated PHPIa, whereas mutations on the paternal allele usually cause PPHP. Isolated PTH resistance (PHPIb) can result from mutations within the GNAS1 gene but is more commonly caused by epigenetic imprinting abnormalities affecting the upstream exon 1A. The causes of PHP type Ic and PHP type II are not yet clear, and the latter is likely to be heterogeneous.

Analysis of the GNAS1 Gene in Albright's Hereditary Osteodystrophy

Analysis of the GNAS1 Gene in Albright's Hereditary Osteodystrophy

A Case of Albright's Hereditary Osteodystrophy-Like Syndrome Complicated by Several Endocrinopathies: Normal Gs Gene and Chromosome 2q37

A Case of Albright's Hereditary Osteodystrophy-Like Syndrome Complicated by Several Endocrinopathies: Normal Gs Gene and Chromosome 2q37