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Children (Basel, Switzerland) May 2022Pseudohypoparathyroidism (PHP) is a rare, heterogeneous disorder characterized by end-organ resistance to parathyroid hormone (PTH). PTH resistance causes elevated PTH...
Pseudohypoparathyroidism (PHP) is a rare, heterogeneous disorder characterized by end-organ resistance to parathyroid hormone (PTH). PTH resistance causes elevated PTH levels, hypocalcemia, and hyperphosphatemia. Since hypocalcemia causes life-threatening events, early diagnosis is crucial. However, the diagnosis of PHP is elusive during infancy because PHP is usually diagnosed with hypocalcemia-induced symptoms, which develop later in childhood when calcium requirements increase. A 1-month-old girl was referred to our clinic for elevated thyroid-stimulating hormone (TSH) levels on newborn screening. When measured 1 month after levothyroxine treatment, her TSH level normalized. At 4-months-old, multiple hard nodules were noted on her trunk. A punch skin biopsy revealed osteoma cutis associated with Albright's hereditary osteodystrophy, a major characteristic of PHP. We performed targeted sanger sequencing of the gene and detected a heterozygous variant c.150dupA (p.Ser51Ilefs*3) in both the proband and her mother, causing frameshift and premature termination mutations. The patient was diagnosed with PHP Ia when she had normal calcium, phosphorous, and PTH levels. We report the early diagnosis of PHP Ia without hypocalcemia. It emphasizes the importance of meticulous physical examination in patients with congenital hypothyroidism.
PubMed: 35626900
DOI: 10.3390/children9050723 -
Frontiers in Endocrinology 2022This study aimed to present the spectrum of thyroid dysfunction, including hormonal and ultrasound aspects, in a cohort of paediatric and adult patients diagnosed with...
New insights into thyroid dysfunction in patients with inactivating parathyroid hormone/parathyroid hormone-related protein signalling disorder (the hormonal and ultrasound aspects): One-centre preliminary results.
OBJECTIVE
This study aimed to present the spectrum of thyroid dysfunction, including hormonal and ultrasound aspects, in a cohort of paediatric and adult patients diagnosed with inactivating parathyroid hormone (PTH)/PTH-related protein signalling disorders 2 and 3 (iPPSD).
METHODS
The medical records of 31 patients from 14 families diagnosed with iPPSD between 1980 and 2021 in a single tertiary unit were retrospectively analysed. Biochemical, hormonal, molecular, and ultrasonographic parameters were assessed.
RESULTS
In total, 28 patients from 13 families were diagnosed with iPPSD2 (previously pseudohypoparathyroidism [PHP], PHP1A, and pseudo-PHP) at a mean age of 12.2 years (ranging from infancy to 48 years), and three patients from one family were diagnosed with iPPSD3 (PHP1B). Thyroid dysfunction was diagnosed in 21 of the 28 (75%) patients with iPPSD2. Neonatal screening detected congenital hypothyroidism (CH) in 4 of the 20 (20%) newborns. The spectrum of thyroid dysfunction included: CH, 3/21 (14.2%); CH and autoimmune thyroiditis with nodular goitre, 1/21 (4.8%); subclinical hypothyroidism, 10/21 (47.6%); subclinical hypothyroidism and nodular goitre, 1/21 (4.8%); primary hypothyroidism, 4/21 (19%); and autoimmune thyroiditis (Hashimoto and Graves' disease), 2/21 (9.6%). Thyroid function was normal in 7 of the 28 (25%) patients with iPPSD2 and in all patients with iPPSD3. Ultrasound evaluation of the thyroid gland revealed markedly inhomogeneous echogenicity and structure in all patients with thyroid dysfunction. Goitre was found in three patients.
CONCLUSION
The spectrum of thyroid dysfunction in iPPSD ranges from CH to autoimmune thyroiditis and nodular goitre. Ultrasonography of the thyroid gland may reveal an abnormal thyroid parenchyma.
Topics: Adult; Child; Congenital Hypothyroidism; Goiter, Nodular; Graves Disease; Humans; Infant, Newborn; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Retrospective Studies; Thyroid Diseases; Thyroiditis, Autoimmune; Ultrasonography
PubMed: 36213284
DOI: 10.3389/fendo.2022.1012658 -
The Pan African Medical Journal 2019Albright's hereditary osteodystrophy is a rare disease, characterized by phosphocalcic balance abnormalities related to peripheral resistance to parathyroid hormone. It...
Albright's hereditary osteodystrophy is a rare disease, characterized by phosphocalcic balance abnormalities related to peripheral resistance to parathyroid hormone. It is an hereditary affection with autosomal dominant inheritance pattern caused by mutation in GNAS gene1. It combines specific morphotype, subcutaneous calcifications, bone and renal resistance to parathyroid hormone. We report a new case of Albright's hereditary osteodystrophy in a 9-month old infant followed up for significant hypocalcaemia which occurred at 10 days of life. The purpose of this study was to remind clinicians of the clinical, biological, genetic and therapeutic features of this disease.
Topics: Follow-Up Studies; Humans; Hypocalcemia; Infant; Male; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 32180864
DOI: 10.11604/pamj.2019.34.190.13398 -
JBMR Plus Jan 2022Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of , a complex locus that encodes the alpha-stimulatory subunit of heterotrimeric G...
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of , a complex locus that encodes the alpha-stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to and α due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein-coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid-stimulating hormone [TSH], growth hormone-releasing hormone [GHRH], calcitonin) and severe obesity. Paternally-inherited mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally-inherited () versus maternally-inherited () mutations, and these findings were observed predominantly in female mice. Specifically, mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between and mice could potentially be related to changes in the bone microenvironment driven by calcitonin-resistance within osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast-osteoclast coupling. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 35079678
DOI: 10.1002/jbm4.10570 -
Bone Reports Jun 2021Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) (Inactivating PTH/PTHrP Signaling Disorders type 2, IPPSD2) are two rare autosomal...
A novel synonymous variant in exon 1 of gene results in a cryptic splice site and causes pseudohypoparathyroidism type 1A and pseudo-pseudohypoparathyroidism in a French family.
INTRODUCTION
Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) (Inactivating PTH/PTHrP Signaling Disorders type 2, IPPSD2) are two rare autosomal disorders caused by loss-of-function mutations on either maternal or paternal allele, respectively, in the imprinted gene, which encodes the α subunit of the ubiquitously-expressed stimulatory G protein (Gαs).
CASE PRESENTATION
We investigated a synonymous variant NM_001077488.2: c.108C>A / p.(Val36=) identified in a family presenting with IPPSD2 phenotype. splicing prediction algorithms were in favor of a deleterious effect of this variant, by creating a new donor splicing site. The expression studies in blood suggested haploinsufficiency and showed an alternate splice product demonstrating the unmasking of a cryptic site, leading to a 34 base pairs deletion and the creation of a probable unstable RNA.We present the first familial case of IPPSD2 caused by a pathogenic synonymous variant in gene.
PubMed: 33997150
DOI: 10.1016/j.bonr.2021.101073 -
Indian Journal of Clinical Biochemistry... Oct 2019Pseudohypoparathyroidism (PHP) is a state of parathyroid hormone resistance and is characterised by low serum calcium, and elevated serum phosphate and parathyroid...
Pseudohypoparathyroidism (PHP) is a state of parathyroid hormone resistance and is characterised by low serum calcium, and elevated serum phosphate and parathyroid hormone level. Association of PHP with autoimmune disorders is rare and seldom reported in the literature. Here we describe a case of PHP who subsequently developed multiple autoimmune disorders (type 3 polyglandular autoimmune syndrome), which has not been reported so far.
PubMed: 31686738
DOI: 10.1007/s12291-018-0802-6 -
Intractable & Rare Diseases Research Aug 2020Symptomatic hypocalcemia is frequently encountered in the Emergency Department, necessitating admission. It has a variety of underlying etiologies, with...
Symptomatic hypocalcemia is frequently encountered in the Emergency Department, necessitating admission. It has a variety of underlying etiologies, with hypoparathyroidism and vitamin D deficiency being the most common. However, rarer etiologies such as pseudohypoparathyroidism, as was present in the current case, should not be overlooked. Reported here is a case of a young female patient presenting with generalized tonic clonic seizures. Electrocardiography revealed a prolonged QT interval which pointed towards a metabolic cause, and this was confirmed by laboratory results which indicated a low calcium level. A parathyroid pathology was obvious as the phosphate level was elevated. Pseudohypoparathyroidism, rather than hypoparathyroidism, was identified since the parathyroid hormone level was elevated. Other relevant differential diagnoses were excluded. The patient was treated with intravenous calcium initially and given regular oral calcium, calcitriol, and sevelamer.
PubMed: 32844075
DOI: 10.5582/irdr.2020.03014 -
Journal of Pediatric Genetics Mar 2021Ectopic calcification in soft tissue is associated with several disorders including pseudohypoparathyroidism (PHP), which is characterized by resistance or nonresponse...
Ectopic calcification in soft tissue is associated with several disorders including pseudohypoparathyroidism (PHP), which is characterized by resistance or nonresponse to parathyroid hormone (PTH) function. Association between PHP and 22q11DS, also known as DiGeorge syndrome, is rare, especially in children. We describe a newborn girl diagnosed with 22q11DS, presenting ectopic calcifications in soft tissue and suspicion of PHP. PTH function showed values close to the upper limit of the reference value. Radiology showed bone callus in the right wrist. PHP can be a new clinical finding associated with 22q11DS. Parathyroid function investigation in individuals with 22q11DS, presenting bone dysmorphisms and/or calcium metabolism alterations, should be considered.
PubMed: 33552638
DOI: 10.1055/s-0040-1701640 -
Italian Journal of Pediatrics Mar 2021Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly...
BACKGROUND
Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies.
METHODS
Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice.
RESULTS
In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism.
CONCLUSIONS
The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.
Topics: Child; Consensus; Critical Pathways; Female; Follow-Up Studies; Humans; Italy; Male; Practice Patterns, Physicians'; Pseudohypoparathyroidism; Surveys and Questionnaires
PubMed: 33663571
DOI: 10.1186/s13052-021-01000-z -
BMC Pediatrics Aug 2022Primary adrenal insufficiency in children has non-specific and extensive clinical features, so the diagnosis of its etiology is complex and challenging. Although...
BACKGROUND
Primary adrenal insufficiency in children has non-specific and extensive clinical features, so the diagnosis of its etiology is complex and challenging. Although congenital adrenal hyperplasia is the most common cause, more and more other genetic causes have been identified. GNAS mutation is easily overlooked as a rare cause of primary adrenal insufficiency. Here we firstly report a neonatal case of primary adrenal insufficiency caused by GNAS mutation.
CASE PRESENTATION
A boy was diagnosed with congenital hypothyroidism 10 days post-partum and treated immediately. He also had persistent hyperkalaemia and hyponatraemia with elevated adrenocorticotropic hormone. At 70 days after birth, he was transferred to our hospital on suspicion of congenital adrenal hyperplasia. Physical examination found no other abnormalities except for growth retardation. Laboratory examination revealed increased aldosterone and normal cortisol, 17-hydroxyprogesterone, and androstenedione levels. Abnormally elevated parathyroid hormone was accompanied by normal blood calcium. Genetic assessment found a de novo, heterozygous c.432 + 1G > A variant in GNAS.
CONCLUSIONS
We report this case to highlight that GNAS mutation is an unusual cause of primary adrenal insufficiency. The combination of primary hypothyroidism and /or pseudohypoparathyroidism will provide diagnostic clues to this condition.
Topics: Addison Disease; Adrenal Hyperplasia, Congenital; Child; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Humans; Infant, Newborn; Male; Mutation
PubMed: 35927642
DOI: 10.1186/s12887-022-03517-6