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European Journal of Endocrinology Jul 2023Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder... (Observational Study)
Observational Study
BACKGROUND
Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height.
OBJECTIVE
Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls.
METHODS
We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models.
RESULTS
Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy.
CONCLUSION
Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.
Topics: Humans; Adult; Growth Hormone; Retrospective Studies; Human Growth Hormone; Pseudohypoparathyroidism; Dwarfism, Pituitary; Hypopituitarism; Mutation; Body Height; Recombinant Proteins; Growth Disorders; Chromogranins; GTP-Binding Protein alpha Subunits, Gs
PubMed: 37440712
DOI: 10.1093/ejendo/lvad085 -
Child's Nervous System : ChNS :... Dec 2023The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a... (Review)
Review
PURPOSE
The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a review of the literature in an effort to understand management for this rare entity.
METHODS
Retrospective review of the electronic medical record database was performed to identify patients with primary metabolic bone disorders who underwent craniosynostosis surgery between 2011 and 2022 at a quaternary referral pediatric hospital. Literature review was conducted for primary metabolic bone disorders associated with craniosynostosis.
RESULTS
Ten patients were identified, 6 of whom were male. The most common bone disorders were hypophosphatemic rickets (n = 2) and pseudohypoparathyroidism (n = 2). The median age at diagnosis of metabolic bone disorder was 2.02 years (IQR: 0.11-4.26), 2.52 years (IQR: 1.24-3.14) at craniosynostosis diagnosis, and 2.65 years (IQR: 0.91-3.58) at the time of surgery. Sagittal suture was most commonly fused (n = 4), followed by multi-suture craniosynostosis (n = 3). Other imaging findings included Chiari (n = 1), hydrocephalus (n = 1), and concurrent Chiari and hydrocephalus (n = 1). All patients underwent surgery for craniosynostosis, with the most common operation being bifronto-orbital advancement (n = 4). A total of 5 patients underwent reoperation, 3 of which were planned second-stage surgeries and 2 of whom had craniosynostosis recurrence.
CONCLUSIONS
We advocate screening for suture abnormalities in children with primary metabolic bone disorders. While cranial vault remodeling is not associated with a high rate of postoperative complications in this patient cohort, craniosynostosis recurrences may occur, and parental counseling is recommended.
Topics: Child, Preschool; Female; Humans; Infant; Male; Bone Diseases, Metabolic; Craniosynostoses; Familial Hypophosphatemic Rickets; Hydrocephalus; Retrospective Studies; Skull
PubMed: 37420034
DOI: 10.1007/s00381-023-06059-z -
The Journal of the Association of... Mar 2023Awareness regarding the etiological spectrum of tetany is poor among physicians. Because of poor awareness, tetany is underdiagnosed and undertreated.
INTRODUCTION
Awareness regarding the etiological spectrum of tetany is poor among physicians. Because of poor awareness, tetany is underdiagnosed and undertreated.
MATERIALS AND METHODS
Databases like PubMed, PubMed Central, Scopus, and Google Scholar are searched to identify peer-reviewed articles on tetany. Case reports, case series, and original articles are analyzed to identify different causes of tetany prevalent in the community. Different causes found are analyzed and tabulated, and finally, a flowchart is made on the approach for diagnosing different underlying pathologies of tetany.
RESULTS
Both metabolic and respiratory alkalosis are important causes of tetany because of reduced ionized calcium levels. Gitelman syndrome (GS) is associated with metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria, and frequently causes normocalcemic tetany. Recurrent vomiting and primary hyperaldosteronism also cause tetany due to metabolic alkalosis. Hyperventilation syndrome (HVS) leads to respiratory alkalosis and is a frequent cause of tetany. Hyperventilation-induced tetany is also seen after spinal anesthesia and in respiratory disorders like asthma. Vitamin D deficiency (VDD), primary hypoparathyroidism, and pseudohypoparathyroidism (PHP) (1a, 1b, and 2) cause hypocalcemic tetany. Hypomagnesemia causes hypocalcemia and tetany due to peripheral parathyroid hormone resistance and impaired parathyroid hormone secretion. Drugs causing tetany include bisphosphonates, denosumab, cisplatin, antiepileptics, aminoglycosides, diuretics, etc. Tetany is also seen in acute pancreatitis, dengue, falciparum malaria, hyperemesis gravidarum, tumor lysis syndrome (TLS), massive blood transfusion, etc. Conclusion: The spectrum of disorders associated with tetany is diverse. Awareness of different causes will help early and proper diagnosis of tetany.
Topics: Humans; Tetany; Alkalosis, Respiratory; Hyperventilation; Acute Disease; Pancreatitis; Hypocalcemia; Alkalosis; Magnesium; Parathyroid Hormone; Calcium
PubMed: 37354510
DOI: 10.5005/japi-11001-0203 -
Clinical Genetics Sep 2023The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus.... (Review)
Review
The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.
Topics: Humans; Animals; Mice; Bone Density; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Pseudohypoparathyroidism; Mutation
PubMed: 37249323
DOI: 10.1111/cge.14378 -
The Journal of the Association of... Jan 2023Symptomatic hypocalcemia has a variety of underlying etiologies,with hypoparathyroidism and vitamin D deficiency being the most common. However,rarer etiologies such as...
INTRODUCTION
Symptomatic hypocalcemia has a variety of underlying etiologies,with hypoparathyroidism and vitamin D deficiency being the most common. However,rarer etiologies such as pseudohypoparathyroidism, as is present in the current case, should not be overlooked. Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by parathyroid hormone (PTH) resistance. The diagnosis of this rare genetic condition is often delayed,due to its myriad presentations,leading to an initially inappropriate approach and therapy.
MATERIALS
A 19-year-old male,K/C/O seizure disorder since 18 years,presented to ER in generalized convulsive status epilepticus since 2 hours.Developmentally he had poor growth spurt. No h/o trauma, fever, vomiting, headache. Patient continued to have seizures occasionally despite being compliant to Tab Sodium Valproate 250mg BD.O/E: Patient was drowsy but arousable. He had short stature.Height-35 kg, Weight-136 cm and BMI 18.92 kg/m2.Bilateral cataractous lens+. Examination of limbs revealed brachydactyly of the fingers and fourth toes. Chvostek and Trousseau signs were positive. Knuckle knuckle Dimple Dimple Sign+ Result: ECG showed showed prolonged QT interval. Blood investigations showed Serum calcium-5.8, Serum phosphorus-8.7, iPTH-193, TSH-15.4. MRI brain revealed diffuse bilateral calcifications of basal ganglia. Given the clinical,radiographic and laboratory findings, diagnoses of PHP type Ia with primary hypothyroidism was made.Patient was admitted to wards,hypocalcemia corrected with intravenous and oral calcium and vitamin D.Discharged on 50 ug levothyroxine, oral calcium, vitamin D3 oral solution weekly. The patient is being followed up at half monthly intervals and has remained seizure free since discharge.
CONCLUSION
PHP type Ia (GNAS gene mutation) is the most common form of PHP and associated with Albright's hereditary osteodystrophy (AHO), resistance to multiple hormones. This case stresses the pivotal role of a complete biochemical investigation of the calcium phosphate metabolism in every References Melmed S, Koenig R, Rosen C, Auchus R, Goldfine A. Williams textbook of endocrinology: South Asia edition, 2 vol set-E-book. Elsevier India; 2020 Jun 30. Mantovani G, Bastepe M, Monk D, De Sanctis L, Thiele S, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T. Recommendations for diagnosis and treatment of pseudohypoparathyroidism and related disorders: an updated practical tool for physicians and patients. Hormone research in paediatrics. 2020;93(3):182-96.
Topics: Humans; Male; Child; Young Adult; Adult; Calcium; Hypocalcemia; Pseudohypoparathyroidism; Vitamin D; Vitamins; Calcinosis; Calcium, Dietary
PubMed: 37116029
DOI: No ID Found -
The Journal of Clinical Endocrinology... Oct 2023Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical...
BACKGROUND
Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical features including obesity, neurocognitive impairment, brachydactyly, short stature, parathyroid hormone (PTH) resistance, and resistance to other hormones such as thyroid-stimulating hormone (TSH) have been well described, yet they refer mainly to the full development of the disease during late childhood and adulthood.
OBJECTIVE
A significant delay in diagnosis has been reported; therefore, our objective is to increase awareness on neonatal and early infancy presentation of the diseases. To do so, we analyzed a large cohort of iPPSD/PHP patients.
METHODS
We included 136 patients diagnosed with iPPSD/PHP. We retrospectively collected data on birth and investigated the rate of neonatal complications occurring in each iPPSD/PHP category within the first month of life.
RESULTS
Overall 36% of patients presented at least one neonatal complication, far more than the general population; when considering only the patients with iPPSD2/PHP1A, it reached 47% of the patients. Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, ie, 10.5% and 18.4%, respectively. The presence of neonatal features was associated with earlier resistance to TSH (P < 0.001) and with the development of neurocognitive impairment (P = 0.02) or constipation (P = 0.04) later in life.
CONCLUSION
Our findings suggest that iPPSD/PHP and especially iPPSD2/PHP1A newborns require specific care at birth because of an increased risk of neonatal complications. These complications may predict a more severe course of the disease; however, they are unspecific which likely explains the diagnostic delay.
Topics: Humans; Infant; Infant, Newborn; Chromogranins; Delayed Diagnosis; GTP-Binding Protein alpha Subunits, Gs; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Rare Diseases; Retrospective Studies; Thyrotropin
PubMed: 37098127
DOI: 10.1210/clinem/dgad236 -
Kathmandu University Medical Journal... 2022Hypocalcaemia of various origin can be manifested by paresthesia, muscle cramps, muscle weakness, syncope, convulsions and even severe psychomotor retardation. Such...
Hypocalcaemia of various origin can be manifested by paresthesia, muscle cramps, muscle weakness, syncope, convulsions and even severe psychomotor retardation. Such symptoms can be initially considered as signs of epilepsy. We present a 12- year old boy with partial seizures and basal ganglia calcifications, initially diagnosed as having Fahr´s disease and epilepsy, where severe hypocalcaemia, due to genetically confirmed pseudohypoparathyroidism type Ib was the underlying cause. Excellent clinical improvement was observed after calcium and vitamin D therapy. The basal ganglia calcifications were secondary due to chronic hypocalcaemia, therefore the appropriate diagnosis was pseudohypoparathyroidism type Ib with Fahr´s syndrome, but not Fahr´s disease. In conclusion, the serum evaluation of minerals, especially calcium and phosphate, should be performed in all patients with convulsions, cramps and psychomotor retardation. This is essential in arriving at a proper diagnosis and early initiation of appropriate treatment.
Topics: Male; Humans; Child; Hypocalcemia; Calcium; Pseudohypoparathyroidism; Seizures; Epilepsy
PubMed: 37042384
DOI: No ID Found -
Current Osteoporosis Reports Jun 2023Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia,... (Review)
Review
PURPOSE OF REVIEW
Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. PHP is divided into several subtypes with different yet overlapping phenotypes. Research on the bone status in patients with PHP is sparse and has yielded inconsistent results. This review was performed to summarize the current knowledge on the bone phenotypes and possible mechanisms of PHP.
RECENT FINDINGS
Patients with PHP exhibit highly variable bone phenotypes and increased concentrations of bone turnover markers. Long-standing elevation of the parathyroid hormone concentration may lead to hyperparathyroid bone diseases, including rickets and osteitis fibrosa. Compared with normal controls, patients with PHP may exhibit similar, increased, or decreased bone mineral density. Higher bone mineral density has been found in patients with PHP type 1A than in normal controls, whereas decreased bone mass, osteosclerosis, and osteitis fibrosa cystica have been reported in patients with PHP type 1B, indicating more variable bone phenotypes in PHP type 1B. Bone tissues show partial sensitivity to parathyroid hormone in patients with PHP, leading to heterogeneous reactions to parathyroid hormone in different individuals and even in different regions of bone tissues in the same individual. Regions rich in cancellous bone are more sensitive and show more obvious improvement after therapy. Active vitamin D and calcium can significantly improve abnormal bone metabolism in patients with PHP.
Topics: Humans; Bone and Bones; Pseudohypoparathyroidism; Parathyroid Hormone; Bone Diseases; Phenotype; GTP-Binding Protein alpha Subunits, Gs; Chromogranins
PubMed: 37014531
DOI: 10.1007/s11914-023-00787-6 -
Medical Archives (Sarajevo, Bosnia and... Feb 2023Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). (Review)
Review
BACKGROUND
Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia).
OBJECTIVE
The aim of this article was to present 9 months old male patient as case of congenital hypothyroidism.
CASE REPORT
We describe a 9 months old male diagnosed with congenital hypothyroidism at age 1.5 month, who developed later (at age 5 months) cyanotic attack associated with hypocalcaemia, hyperphosphatemia, and hyperparathyroidism, patient had typical characters of AHO, so the diagnosis of Pseudohypoparathyroidism 1a associated with resistance (TSH) was established.
CONCLUSION
Children diagnosed with PHP 1a should be further evaluated for associated resistance endocrinopathies. The literature on pseudohypoparathyroidism is reviewed with special emphasis on the misdiagnosis with congenital hypothyroidism.
Topics: Humans; Infant; Male; Chromogranins; Congenital Hypothyroidism; Diagnostic Errors; GTP-Binding Protein alpha Subunits, Gs; Pseudohypoparathyroidism
PubMed: 36923733
DOI: 10.5455/medarh.2023.77.70-73 -
Case Reports in Endocrinology 2023Brachymetacarpia and brachymetatarsia are unique clinical entities associated with numerous rare conditions. Primary hypoparathyroidism is distinct from...
Brachymetacarpia and brachymetatarsia are unique clinical entities associated with numerous rare conditions. Primary hypoparathyroidism is distinct from pseudohypoparathyroidism and pseudopseudohypoparathyroidism by lacking skeletal changes such as short metacarpals or metatarsals. Here, we present a case of a 64-year-old patient with brachymetacarpia and brachymetatarsia presented with hypocalcemic symptoms and signs, bilateral cataracts, and basal ganglia calcifications, subsequently diagnosed with idiopathic primary hypoparathyroidism. This is a rare case describing such an infrequent observation of brachymetacarpia and brachymetatarsia in primary idiopathic hypoparathyroidism.
PubMed: 36895827
DOI: 10.1155/2023/4149677