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Brain MRI showing hydrocephalus and CM-I.
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A 19-month-old boy was referred for progressive weight gain. His past medical history included congenital hypothyroidism and developmental delay. Physical examination revealed characteristics of Albright Hereditary Osteodystrophy, macrocephaly, and calcinosis cutis. He had hypocalcemia, hyperphosphatemia, and elevated Parathyroid Hormone levels. Ge...
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Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most case without evidence for Albright Hereditary Osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially methylated regions (DMR) within GNAS, whi...
Citations
... It was hypothesized that GH deficiency can lead to underdevelopment of the posterior fossa, thus leading to CM1 formation [47,[54][55][56]. According to the International Consensus statement for pseudohypoparathyroidism and related disorders [2,10], CM1 is mentioned as a possible occurrence in PHP1A based on a small collection of isolated case reports [57][58][59][60]. These reports are intriguing given that GH deficiency has been found in approximately 70% of PHP1A patients secondary to GHRH resistance [4,17,18]. ...
... This is much greater than the frequency of GH deficiency in the general population of 1:3,480 [61]. In alignment with these findings, two recent case reports describe PHP1A patients who developed CM1 and were GH deficient [57,60]. In both of these isolated reports, the authors hypothesized that the development of CM1 was secondary to inappropriate cartilage growth at the cranial base due to GH deficiency. ...
... When evaluating for various independent risk factors, we did not observe any correlation between the frequency of CM1 or LLCT development and biological sex, GNAS mutation severity, bone age advancement, or GH status. Our findings regarding the lack of correlation to GH status are intriguing in light of a collection of isolated case reports that hypothesized GH deficiency as a possible cause of CM1 in PHP1A [57,60], as well as numerous reports suggesting that GH deficiency plays a role in CM1 formation in the general population [47,48]. We acknowledge that there may be sampling bias in our investigation given that 75% of our participants had brain MRIs performed secondary to GH deficiency on stimulation testing (as part of standard of care). ...
Background:
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model.
Methods:
We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A.
Results:
In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A.
Conclusion:
The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.
... We found no additional pathogenic or likely pathogenic variants. Interestingly, CM1 was previously reported in a patient with Eiken syndrome (ES) (18) and in 3 patients with PHP1A (24)(25)(26). The underlying mechanisms have not been elucidated yet but growth hormone pathway alteration might be involved in CM1 associated with PHP1A (25,27). ...
... Interestingly, CM1 was previously reported in a patient with Eiken syndrome (ES) (18) and in 3 patients with PHP1A (24)(25)(26). The underlying mechanisms have not been elucidated yet but growth hormone pathway alteration might be involved in CM1 associated with PHP1A (25,27). ...
PTH resistance is characterized by elevated parathyroid hormone (PTH) levels, hypocalcemia, hyperphosphatemia and it is classically associated with GNAS locus genetic or epigenetic defects. Inactivating PTH/PTHrP signaling disorders (iPPSD) define overlapping phenotypes based on their molecular etiology. iPPSD1 is associated with PTH1R variants and variable phenotypes including ossification anomalies and primary failure of tooth eruption but no endocrine disorder. Here we report on a 10-month-old child born from consanguineous parents, who presented with mild neurodevelopmental delay, seizures, enlarged fontanelles, round face, and bilateral clinodactyly. Hand x-rays showed diffuse delayed bone age, osteopenia, short metacarpal bones and cone-shaped distal phalanges. A diagnosis of PTH resistance was made on the basis of severe hypocalcemia, hyperphosphatemia, elevated PTH and normal vitamin D levels on blood sample. The patient was treated with calcium carbonate and alfacalcidol leading to rapid bio-clinical improvement. Follow-up revealed multiple agenesis of primary teeth and delayed teeth eruption, as well as Arnold-Chiari type 1 malformation requiring a ventriculoperitoneal shunt placement. GNAS gene analysis showed no pathogenic variation, but a likely pathogenic homozygous substitution c.723C>G p.(Asp241Glu) in PTH1R gene was found by trio-based whole exome sequencing. We studied the deleterious impact of the variant on the protein conformation with bioinformatics tools. In conclusion, our study reports for the first time PTH resistance in a child with a biallelic PTH1R mutation, extending thereby the clinical spectrum of iPPSD1 phenotypes.
... Association of neurologic dysfunction with PHP1A is not well appreciated. Two cases on the association of PHP1A and CM-1 have been reported in the literature [4,5]. Martínez-Lage et al. reported a girl with PHP1A who also complained of mild headache, with imaging showing cerebellar tonsillar descent. ...
... In another report by Kashani et al., a younger patient with PHP1A had MRI brain performed for evaluation of developmental delay at 34 months, which revealed CM-1 with hydrocephalus requiring neurosurgical intervention. Similar to our patient, he had a normal MRI brain earlier in life [5]. ese cases demonstrated that CM-1 may develop with time presenting with nonspecific symptoms, and hence, a low threshold in performing brain imaging should be adopted. ...
Background:
While the endocrine manifestations of pseudohypoparathyroidism are well known, less is known about the associated brain and spine abnormalities. These abnormalities may present with nonspecific symptoms in the paediatric population, and lack of awareness to these uncommon manifestations of the disease may result in a delay in necessary intervention. Case Presentation. We herein present a case of known pseudohypoparathyroidism type 1a who presented initially with minor head injury. She later developed progressive worsening headache, increased irritability, and vomiting. Repeated imaging showed hydrocephalus and Chiari malformation type 1 necessitating emergency craniectomy.
Conclusion:
Growth hormone deficiency, a common manifestation of pseudohypoparathyroidism type 1a, results in underdevelopment of the posterior cranial fossa and may account for the higher incidence of Chiari malformation in this group of patients. Other associated neurological features reported in pseudohypoparathyroidism type 1a include spinal stenosis, syringomyelia, and craniosynostosis. While less commonly seen, awareness to these associations is important in order to optimize the multidisciplinary care to this group of patients.
... One retrospective review of developmental milestones showed a greater delay in language compared with gross motor skills, with and a tendency to improve during late childhood [6]. Neurological and neuropsychiatric manifestations can be linked to the function in addition to the role of Gsα in brain development [84], and other organic CNS alterations, including Chiari 1 malformation [85][86][87] or prolonged periods of hypocalcemia [83,87] found in some patients. Patients with PHP and related disorders should be referred to a neuropsychologist for neurocognitive and/or behavioral assessment at diagnosis or at preschool age, especially patients with PHP1A and acrodysostosis due to PDE4D pathogenic variants mutations. ...
Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
... Additional features have been described in patients with PHP1A. For instance, affected patients are born with a moderately reduced birth length that usually does not prompt investigations 24,30,[36][37][38] . Obesity might develop in very early life and be recognized before any endocrine disturbances appear in early childhood 30,35,39 . ...
... Intellectual disability seems to be more prevalent in patients with PHP1A than in patients with PPHP, which suggests that G s α is imprinted in the brain 24,214,229 . The existence of neurological manifestations or true neuropsychiatric phenotype due to organic CNS alterations, and specifically Chiari malformation type 1, should be considered 38,207,265 . Finally, the prevalence and severity of cognitive impairment and developmental delay vary among patients with acrodysostosis, but a detailed clinical description is lacking 5,6,14,63,266 . ...
This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.
... Additional features have been described in patients with PHP1A. For instance, affected patients are born with a moderately reduced birth length that usually does not prompt investigations 24,30,[36][37][38] . Obesity might develop in very early life and be recognized before any endocrine disturbances appear in early childhood 30,35,39 . ...
... Intellectual disability seems to be more prevalent in patients with PHP1A than in patients with PPHP, which suggests that G s α is imprinted in the brain 24,214,229 . The existence of neurological manifestations or true neuropsychiatric phenotype due to organic CNS alterations, and specifically Chiari malformation type 1, should be considered 38,207,265 . Finally, the prevalence and severity of cognitive impairment and developmental delay vary among patients with acrodysostosis, but a detailed clinical description is lacking 5,6,14,63,266 . ...
Since Albright and co-workers described pseudohypoparathyroidism in 1942 as the combined presence of hypocalcaemia and hyperphosphataemia associated with the existence of tissue resistance to parathyroid hormone (PTH) action upon normal renal function, great advances have been made in the clinical and genetic profile of patients affected by this condition. Furthermore, not only have genetic bases of pseudohypoparathyroidism been unravelled, but also variants in other genes involved in the PTH/PTHrP signalling pathway through Gsα, have been identified as the cause of diseases that share clinical features with pseudohypoparathyroidism. In the paediatric setting, the first symptoms suggesting the impairment of this signalling pathway are the presence of subcutaneous ossifications, brachydactyly and/or early onset obesity, followed by the possible development of PTH resistance. This clinical suspicion should be confirmed by an accurate molecular diagnosis to allow for coordinated multidisciplinary clinical management. Among the features of this group of disorders, physicians should pay attention to evaluation of PTH and/or thyrotropin (TSH) resistance at diagnosis and throughout follow-up, as well as growth hormone deficiency, hypogonadism, skeletal deformities, dental impairment, obesity, insulin resistance, impaired glucose tolerance or type 2 diabetes mellitus and hypertension, as well as ectopic ossifications (either subcutaneous or affecting deeper tissues) and impairment of neurocognitive development.
Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.
Pseudohypoparathyroidism (PHP) and related disorders encompass a series of disorders that impair the cAMP signaling pathway downstream of the receptor for PTH/PTHrP, and several other Gsα‐coupled receptors. PHP1A is an autosomal dominant disease caused by inactivating mutations that involve the maternal GNAS exons encoding Gsα. Some years after the initial description of PHP1, asymptomatic relatives of patients with PHP1A were identified who showed typical features of Albright hereditary osteodystrophy (AHO) but lacked PTH resistance. Acrodysostosis is a chondrodysplasia that includes severe brachydactyly, facial dysostosis, and nasal hypoplasia, features that can also be found in AHO. Progressive osseous heteroplasia (POH) patients display few if any other AHO features, and typically do not develop PTH resistance. POH is characterized by extensive and clinically significant ossifications that are present in the skin as well as in the deep connective tissue.
