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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 -
JCEM Case Reports Jul 2023PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is...
PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is subdivided into different types according to its different pathogenesis and phenotype. PTH receptor is the alpha subunit of stimulatory G protein (Gα)-coupled receptor. Pathogenic variants of GNAS gene, encoding for Gα, lead to reduced Gα function and PTH resistance. We report a patient with PHP type 1a, with no documented evidence of hypocalcemia, presenting with AHO phenotype and multihormone resistance to PTH, TSH, and GnRH. Her genetic testing showed a novel heterozygous pathogenic variants, a c.934T > G change in exon 11 in adenylate cyclase stimulatory G protein that has not been reported in the literature so far.
PubMed: 37908988
DOI: 10.1210/jcemcr/luad088 -
Orphanet Journal of Rare Diseases Nov 2023Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH...
BACKGROUND
Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH resistant have been widely studied, glucolipid metabolism abnormalities observed in PHP1 patients have received little attention. The aim of this research is to explore the glucolipid metabolism features in a rather large cohort of PHP1 patient. In the current study, PHP1 patients and primary hyperparathyroidism patients as well as normal control were recruited for the investigation. Glucolipid metabolic indices as well as the level of four adipokines were examined.
RESULTS
A total of 49 PHP1 patients, 64 PHPT patients and 30 healthy volunteers were enrolled. A trend of higher HOMA-β index was found in PHP1 patients than normal controls (median 97.08% vs 68.19%, p = 0.060). Both the PHP1 and PHPT group presented with significantly lower TNFα level compared to normal controls (average 10.74 pg/ml and 12.53 pg/ml vs 15.47 pg/ml, p = 0.002 and 0.041, respectively). FGF21 level was significantly higher in PHPT group than in PHP1 group (median 255.74 pg/ml vs 167.46 pg/ml, p = 0.019). No significant difference in glucolipid metabolic indices and adipokines was found between PHP1A or PHP1B patients and normal controls, while overweight/obese PHP1 patients tended to have higher leptin than normal-BMI cases (p = 0.055). Multiple linear regression analysis showed BMI rather than PTH or HOMA-IR to be an independent variable of leptin in PHP1.
CONCLUSION
Metabolic stress given upon especially overweight PHP1 patients may resulted in possible β-cell compensation. Elevated TNFα may be related with hyper-PTH level regardless of calcium level.
Topics: Humans; Calcium; Leptin; Adipokines; Tumor Necrosis Factor-alpha; Overweight; Pseudohypoparathyroidism
PubMed: 38017461
DOI: 10.1186/s13023-023-02979-w -
AACE Clinical Case Reports 2021To describe new and unusual endocrinopathies in children with de novo 18q deletion (18q-) syndrome.
OBJECTIVE
To describe new and unusual endocrinopathies in children with de novo 18q deletion (18q-) syndrome.
METHODS
We describe 2 patients who have atypical thyroid conditions and 1 who also developed symptomatic hypocalcemia.
RESULTS
The first patient developed hyperthyroidism at the age of 3 years, with a free thyroxine level of 3.9 (range, 0.8-1.8) ng/dL. Thyroid peroxidase antibodies were 262 (range, 0-32) IU/mL, and thyroid-stimulating immunoglobulin antibodies were 384% (range, 0-139%). On low-dose methimazole treatment, she developed hypothyroidism. Thyroid-stimulating hormone (TSH) level was 163 (range, 0.4-4.5) mIU/mL. Moreover, she later developed growth hormone deficiency. The second patient developed hypothyroidism at the age of 4 years, with a TSH level of 46 mIU/mL. However, TSH remained elevated at levels of 10 to 24 mIU/mL for 3 years, despite appropriate treatment, suggesting TSH resistance. She then developed hypocalcemic seizures and was diagnosed with pseudohypoparathyroidism. Her total calcium level was 6.6 (range, 8.5-10.5) mg/dL and parathyroid hormone level was 432 (range, 15-65) pg/dL.
CONCLUSION
The first patient had a mixed picture of autoimmune hypothyroidism and hyperthyroidism, requiring a combination of methimazole and levothyroxine to achieve a euthyroid state. For the second patient, the mild TSH resistance was possibly the early suggestion of a parathyroid hormone resistant state. Although growth hormone deficiency and hypothyroidism are common in patients with 18q- syndrome, the occurrence of hyperthyroidism due to Graves' disease with the coexistence of Hashimoto's hypothyroidism is rare. Pseudohypoparathyroidism has not yet been reported in patients with 18q- syndrome.
PubMed: 34095486
DOI: 10.1016/j.aace.2020.12.012 -
Child Neurology Open 2023Genetic evaluation of a teenager with seizure found no pathogenic variant in a large gene panel, but an incidental likely pathogenic variant, deemed to cause MODY1...
Genetic evaluation of a teenager with seizure found no pathogenic variant in a large gene panel, but an incidental likely pathogenic variant, deemed to cause MODY1 diabetes. Diabetes history was absent and glycated hemoglobin normal, but serum calcium was severely low, with abnormally high parathyroid hormone. Thus, pseudohypoparathyroidism was suspected and confirmed by molecular genetic testing. Calcium and calcitriol supplementation led to calcium normalization and neurological symptom improvement. Given the absence of personal or family diabetes history, the variant was reassessed and found to encode an alternative transcript with poor expression and activity levels, hence downgraded on expert advice from 'likely pathogenic' to 'likely benign'. Besides illustrating the importance of structured medical workup before launching extensive targeted exome sequencing, this case highlights the need for caution in incidental finding interpretation in patients lacking compatible phenotype or family history, and the value of expert advice in such variant interpretation.
PubMed: 37664540
DOI: 10.1177/2329048X231199327 -
BMC Medical Genetics Sep 2020Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include...
BACKGROUND
Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes.
CASE PRESENTATION
The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability.
DISCUSSION AND CONCLUSIONS
Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.
Topics: Bone and Bones; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic Nucleotide Phosphodiesterases, Type 4; Dysostoses; Follow-Up Studies; Genetic Predisposition to Disease; Intellectual Disability; Interdisciplinary Communication; Osteochondrodysplasias; Patient Care Team; Pseudohypoparathyroidism; Radiography; Time Factors
PubMed: 32993552
DOI: 10.1186/s12881-020-01127-6 -
Frontiers in Genetics 2021encodes the stimulatory G protein alpha-subunit (Gsα) and its large variant XLαs. Studies have suggested that XLαs is expressed exclusively paternally. Thus, XLαs...
encodes the stimulatory G protein alpha-subunit (Gsα) and its large variant XLαs. Studies have suggested that XLαs is expressed exclusively paternally. Thus, XLαs deficiency is considered to be responsible for certain findings in patients with paternal mutations, such as pseudo-pseudohypoparathyroidism, and the phenotypes associated with maternal uniparental disomy of chromosome 20, which comprises . However, a study of bone marrow stromal cells (BMSC) suggested that XLαs could be biallelically expressed. Aberrant BMSC differentiation due to constitutively activating mutations affecting both Gsα and XLαs is the underlying pathology in fibrous dysplasia of bone. To investigate allelic XLαs expression, we employed next-generation sequencing and a polymorphism common to XLαs and Gsα, as well as A/B, another paternally expressed transcript. In mouse BMSCs, Gsα transcripts were 48.4 ± 0.3% paternal, while A/B was 99.8 ± 0.2% paternal. In contrast, XLαs expression varied among different samples, paternal contribution ranging from 43.0 to 99.9%. Sample-to-sample variation in paternal XLαs expression was also detected in bone (83.7-99.6%) and cerebellum (83.8 to 100%) but not in cultured calvarial osteoblasts (99.1 ± 0.1%). Osteoblastic differentiation of BMSCs shifted the paternal XLαs expression from 83.9 ± 1.5% at baseline to 97.2 ± 1.1%. In two human BMSC samples grown under osteoinductive conditions, XLαs expression was also predominantly monoallelic (91.3 or 99.6%). Thus, the maternal contributes significantly to XLαs expression in BMSCs but not osteoblasts. Altered XLαs activity may thus occur in certain cell types irrespective of the parental origin of a defect.
PubMed: 34220953
DOI: 10.3389/fgene.2021.680537 -
Oxford Medical Case Reports Aug 2022Pseudohypoparathyroidism (PHP) is a rare disorder that associates with resistance to parathyroid hormone (PTH). A 21-year old man visited outpatient clinic to treat...
Pseudohypoparathyroidism (PHP) is a rare disorder that associates with resistance to parathyroid hormone (PTH). A 21-year old man visited outpatient clinic to treat previously diagnosed hypothyroidism and vitamin D deficiency. Despite daily 150 mcg of levothyroxine supplement, thyroid-stimulating hormone level was elevated, but thyroid autoantibodies were not detected. He showed features of Albright Hereditary Osteodystrophy and elevated serum PTH level with normal albumin-corrected calcium and phosphorus level. The Ellsworth-Howard test proved the blunted response of urinary phosphorus and cyclic adenosine monophosphate after the infusion of the exogenous PTH, suggesting PTH resistance. DNA analysis revealed a heterozygous mutation in the gene (c.478C > T). Herein, we report a case of PHP type 1a confirmed by clinical, biochemical and molecular analyses. Establishing correct diagnosis of PHP is necessary for efficient therapeutic management.
PubMed: 35991493
DOI: 10.1093/omcr/omac080 -
The Journal of Clinical Endocrinology... Mar 2022Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules....
CONTEXT
Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown.
OBJECTIVE
Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B.
DESIGN
Retrospective analysis.
RESULTS
Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally.
CONCLUSION
Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.
Topics: Chromogranins; DNA Methylation; GTP-Binding Protein alpha Subunits, Gs; Humans; Male; Oogenesis; Pseudohypoparathyroidism; Retrospective Studies
PubMed: 34791361
DOI: 10.1210/clinem/dgab830 -
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