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Chest X-ray for patient 2, at 4 weeks of age, shows generalized osteopenia and numerous multilevel bony callus formations along several contiguous ribs bilaterally, suggesting healing fractures (arrows) involving ribs two to nine on the right and ribs two to seven on the left.
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Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NS...
Citations
... Выраженность данных проявлений определяет продолжительность жизни таких пациентов [36]. Ранее единственным видом лечения неонатального гиперпаратиреоза была тотальная паратиреоидэктомия, однако в настоящее время применение лекарственных препаратов, таких как бисфосфонаты и кальцимиметики, показывает не меньшую эффективность [37]. ...
Parathyroid hormone (PTH) plays a key role in the regulation of calcium-phosphate metabolism. The secretion of PTH is regulated by calcium-sensing receptor (CaSR), which primarily expressed in the parathyroid glands and the renal tubules of the kidney. Increase of calcium concentration in extracellular matrix of cells is causing activation of the CaSR. Activated CaSR inhibits secretion of PTH and increases urinary calcium excretion. All CaSR effects leads to prevent development of hypercalcemia complications. Downregulation of the CASR expression and/or altered CaSR functioning leads to dysregulation of PTH synthesis. It may be the underlying cause of the development of primary and secondary hyperparathyroidism, as well as a number of hereditary diseases associated with loss- and gain-of-function mutations of the CaSR. In this paper we discusses the function of the CaSR in physiology and also the potential mechanisms that can impaired CaSR-induced signaling in various calcitropic diseases.
... There have been 12 case reports of successful treatment of NS-HPT with cinacalcet (with genetically confirmed CASR mutations), and three cases reported a lack of response to cinacalcet. Four of these 12 patients had a heterozygous CASR mutation R185Q (one inherited and three de novo) [85][86][87]; seven with inherited homozygous mutations, including R69H, G613E, and Y789fs [88][89][90][91][92]; one with a compound heterozygous mutation, C582Y and P682L [93]; and a homozygous donor splice site mutation in intron 5 [94]. All three cases reported with no response to cinacalcet were patients with homozygous CASR mutations at D99H, R690H, and R69H [95]. ...
Primary hyperparathyroidism (PHPT), a relatively common disorder characterized by hypercalcemia with raised or inappropriately normal serum parathyroid hormone (PTH) concentrations, may occur as part of a hereditary syndromic disorder or as a non-syndromic disease. The associated syndromic disorders include multiple endocrine neoplasia types 1–5 (MEN1-5) and hyperparathyroidism with jaw tumor (HPT-JT) syndromes, and the non-syndromic forms include familial hypocalciuric hypercalcemia types 1–3 (FHH1-3), familial isolated hyperparathyroidism (FIHP), and neonatal severe hyperparathyroidism (NS-HPT). Such hereditary forms may occur in > 10% of patients with PHPT, and their recognition is important for implementation of gene-specific screening protocols and investigations for other associated tumors. Syndromic PHPT tends to be multifocal and multiglandular with most patients requiring parathyroidectomy with the aim of limiting end-organ damage associated with hypercalcemia, particularly osteoporosis, nephrolithiasis, and renal failure. Some patients with non-syndromic PHPT may have mutations of the MEN1 gene or the calcium-sensing receptor ( CASR ), whose loss of function mutations usually cause FHH1, a disorder associated with mild hypercalcemia and may follow a benign clinical course. Measurement of the urinary calcium-to-creatinine ratio clearance (UCCR) may help to distinguish patients with FHH from those with PHPT, as the majority of FHH patients have low urinary calcium excretion (UCCR < 0.01). Once genetic testing confirms a hereditary cause of PHPT, further genetic testing can be offered to the patients’ relatives and subsequent screening can be carried out in these affected family members, which prevents inappropriate testing in normal individuals.
... 5,10-13 Depending on how the mutation affects the function of the protein and which region it affects, the clinical findings and even the response to treatment may vary. 12,14 Inactivating mutations in CASR lead to dysfunction through several different mechanisms. The expression of the receptor on the cell surface may be impaired, which may result from decreased biosynthesis and/or defects in its trafficking from the endoplasmic reticulum to the cell membrane. ...
... 14 In NSHPT, there are case reports where cinacalcet treatment has been used in the newborn or infant period in the dose range of 0.4 to 9.6 mg/kg/day or at doses of 20-202 mg/m2/day, and it has been observed to be successful. 12,14,19,[24][25][26] A case with NSHPT was also reported regarding the safe use of cinacalcet monotherapy for 8 years up to parathyroidectomy. 17 A case of cinacalcet treatment given on the postnatal second day and treated successfully for 18 months was also reported from our country. ...
Background:
Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia in childhood. Heterozygous Calcium-sensing receptor (CASR) gene mutations cause FHH, and homozygous CASR gene mutations cause neonatal severe primary hyperparathyroidism (NSHPT). Cinacalcet is an allosteric modulator of Calciumsensing receptor (CaSR), and has been used in the treatment of these clinical entities in recent years.
Case:
A 26-month-old boy was examined for a recurrent rash. During the evaluation, hypercalcemia (13.3 mg/ dL), hypophosphatemia (2.3 mg/dL) and inappropriately normal PTH level (67 pg/mL) were observed. Neck and renal ultrasonography were normal. The parathyroid scintigraphy was unremarkable. The patient`s family members were also evaluated, and hypocalciuria (fractional excretion of calcium were 0.01%, 0.04% on two separate tests) was detected concurrently with the patient`s hypercalcemia. The mother`s serum calcium was 10.2 mg/dL, the father`s was 10.6 mg/dL, and the brother`s was 12.8 mg/dL. CASR gene sequencing showed a novel homozygous mutation in exon 4 (c.1057G > A), which had generated a substitution of the amino acid glutamate to lysine at codon 353 (p.Glu353Lys). This mutation was homozygous in the children and heterozygous in the parents. Fluid hydration, furosemide, oral phosphorus, prednisolone, pamidronate and cinacalcet treatments were used in the management of hypercalcemia of the proband. A longer and more effective control was achieved with cinacalcet treatment.
Conclusions:
FHH can be seen in heterozygous as well as homozygous CASR gene mutations. Different clinical findings may occur in different individuals from the same family. Cinacalcet therapy can be used successfully in the treatment of individuals with FHH.
... Neonatal severe primary hyperparathyroidism (NSHPT) is a rare, potentially life-threatening autosomal recessive disease characterized by severe hyperparathyroidism, marked hypercalcemia, and metabolic bone disease. 1 Patients mainly present with poor feeding, failure to thrive, hypotonia, lethargy, polyuria, dehydration, respiratory distress, intestinal dysmotility, and skeletal demineralization during the first few weeks after birth. [2][3][4][5][6] If not promptly diagnosed and treated, NSHPT can be associated with high mortality or irreversible neurodevelopmental, renal, skeletal, or cardiologic complications. 2 Although successful medical management of NSHPT has been recently reported, 3,4 early parathyroidectomy followed by calcium supplementation and regular monitoring of serum calcium and PTH levels has been traditionally recommended as the definite therapy. 2,5,6 However, neuromotor abnormalities may persist even after successful treatment, which warrants the long-term follow-up of these patients. ...
... 8,9 On the contrary, early diagnosis and treatment of NSHPT usually lead to gradual improvement in growth and neurodevelopmental milestones. 3,4,6 Ten years after initial presentation, our patient has mild intellectual disability, microcephaly and he is under treatment for epilepsy. According to his mother, the levels of serum calcium and PTH on occasional laboratory tests performed at earlier age were normal. ...
We present a 10-year follow-up and describe our experience in managing a case of neonatal severe primary hyperparathyroidism (NSHPT) for the first time in Iran. Microcephaly, mental retardation, and epilepsy may be long time sequels of NSHPT. The brain MRI findings are compatible with an old hypoxic–ischemic event.
... If not promptly diagnosed and treated, NSHPT can be associated with high mortality or irreversible neurodevelopmental, renal, skeletal, or cardic complications (2). Although successful medical management of NSHPT has been recently reported (3,4), early parathyroidectomy followed by calcium supplementation and regular monitoring of serum calcium and PTH levels has been traditionally recommended as the definite therapy of NSHPT (2,5,6). However, neuromotor abnormalities may persist even after otherwise successful treatment of NSHPT patients, which warrants the long-term follow-up of these patients (1). ...
... Decreased sensitivity of the CaSR receptors to extracellular calcium results in PTH-hyperproduction and consequently, severe hypercalcemia (1), which can be potentially fatal or associated with severe neurodevelopmental impairments in untreated NSHPT patients (8,9). On the other hand, early diagnosis and treatment of NSHPT usually leads to gradual improvement in growth and neurodevelopmental milestones (3,4,6). ...
We present a 10-year follow-up and describe our experience in managing a case of neonatal severe primary hyperparathyroidism (NSHPT) for the first time in Iran. Microcephaly, mental retardation and epilepsy may be long time sequels of NSHPT and the brain MRI findings are compatible with old hypoxic-ischemic event.
... Though it was not done for our patient, MRI can show a low signal intensity mass on T1-weighted images and intermediate or high signal intensity on T2-weighted images in the case of ectopic parathyroid adenomas [9]. The chest X-ray of our patient showed a bell-shaped chest and wider rib separation similar to another previous case of neonatal hyperparathyroidism, indicating that hyperparathyroidism differential diagnosis should be considered in the case of a bell-shaped chest [10]. The bell-shaped chest was also reported in many other similar cases [11,12]. ...
Familial hyperparathyroidism is a rare, inherited endocrine disorder characterized by abnormally elevated serum calcium due to increased parathyroid hormone levels.
In this case report, we present a two-day-old male newborn who was admitted with severe respiratory distress, hyperparathyroidism, and hypercalcemia with a family history of hyperparathyroidism in his two siblings, both diagnosed in childhood and treated with parathyroidectomy. He was diagnosed with familial hyperparathyroidism without other endocrinopathies. His left parathyroid glands were surgically removed, and post-operatively, his parathyroid hormones and calcium levels normalized. Pathological examination of the removed parathyroid glands confirmed parathyroid hyperplasia.
This is a successfully managed case of familial hyperparathyroidism in the neonatal period. Therefore, as the patient grows up, a close follow-up is recommended for early detection and managing multiple endocrine neoplasia type 1 that may be present later in life.
... Cinacalcet is the only drug approved for use in the medical treatment of hyperparathyroidism and parathyroid carcinoma in adults [9]. Although the safety and efficacy of cinacalcet has not yet been approved by the FDA in the paediatric age group, it has been used for life-saving purposes in many cases of FHH and NSHPT after obtaining informed consent [1,7,[9][10][11][12][13][14][15][16][17][18][19][20][21] (Table I). Although we found a homozygous mutation in our patient that was previously reported to be unresponsive to cinacalcet [7], we were able to achieve normocalcaemia with cinacalcet and a calcium-restricted diet until 13 months of age. ...
Neonatal severe hyperparathyroidism (NSHPT) causes severe hypercalcaemia, metabolic bone disease, and potential neurodevelopmental deficits, all of which can be life-threatening. The use of calcimimetic agents can prevent or delay technically difficult parathyroidectomy in the newborn period. We present a 6-day-old male infant who presented with poor feeding, weight loss, and severe hypotonia. His total serum calcium and parathyroid hormone levels were very high (23.6 mg/dl and 1120 ng/dl, respectively). Based on these findings, the patient was diagnosed with NSHPT and was started on cinacalcet therapy until the genetic analysis results were available. Genetic analysis revealed a previously reported homozygous mutation in the CASR gene that was unresponsive to cinacalcet therapy in the literature. However, a normocalcaemic state unexpectantly occurred, which could be maintained with low calcium formula and cinacalcet therapy up to 13 months of age in the patient. Nevertheless, hypercalcaemia developed 2 months after he started a normal calcium-containing diet. Therefore, the patient underwent total parathyroidectomy at 17 months of age. We would like to emphasize, in light of this case, that cinacalcet treatment may be considered as first-line therapy for delaying parathyroidectomy in all cases with NSHPT, even in those who have an unresponsive cinacalcet CASR gene mutation.
... Infants born with NSHPT are typically treated with bisphosphonates to control hypercalcemia by reducing bone resorption, off-label use of cinacalcet (a CaSRpositive allosteric modulator (PAM) approved widely for secondary hyperparathyroidism in chronic kidney disease as well as primary hyperparathyroidism in some countries), and total parathyroidectomy if, as is frequently the case, serum Ca 2+ o and PTH concentrations remain elevated (Mayr et al. 2016). In both NSHPT and some more severe FHH1 cases, cinacalcet demonstrates efficacy in some patients (Timmers et al. 2006, Alon & VandeVoorde 2010, Reh et al. 2011, Wilhelm-Bals et al. 2012, Gannon et al. 2014, Gunganah et al. 2014, Mastromatteo et al. 2014, Fisher et al. 2015, Sun et al. 2018. Cinacalcet potentiates Ca 2+ o -mediated CaSR activation at loss-offunction mutants and can pharmacochaperone some loss-of-expression mutants to the cell surface (Leach et al. 2013). ...
... Naturally occurring mutations were chosen to represent those previously identified to differentially respond to CaSR activators, either clinically or in vitro. These include NSHPT-associated CaSR mutations, where cinacalcet was clinically effective (heterozygous R185Q) (Reh et al. 2011, Gannon et al. 2014, Fisher et al. 2015, Forman et al. 2019, ineffective (homozygous deletion of CASR exon 5 encoding ECD amino acids 460-536, herein referred to as Δ exon 5) (Ahmad et al. 2017, Capozza et al. 2018, or have variable effects (homozygous I81K) (Kahvecioglu et al. 2014, Sun et al. 2018); FHH1-associated mutations for which cinacalcet was ineffective (heterozygous C582R or P798T, homozygous R680H) (Lam et al. 2005, Schnabel et al. 2014. The CaSR structure and PAM binding sites and mutations studied are shown in Fig. 1B. ...
... Cinacalcet (2.4-7.4 mg/kg/day patient 1, 1.68-2.7 mg/kg/day patient 2) normalized serum calcium and PTH (Fisher et al. 2015); f Cinacalcet (0.5-5 mg/kg/day) normalized serum calcium and PTH (Forman et al. 2019); g Cinacalcet (60 mg/day) increased urinary calcium excretion but did not reduce serum calcium ); h Cinacalcet (0.4-4 mg/kg/day) improved but did not resolve hypercalcemia (Capozza et al. 2018); i Cinacalcet (4 mg/kg/day) improved but did not resolve hypercalcemia (Ahmad et al. 2017); j Cinacalcet (0.25-2.5 mg/kg/day) did not sufficiently decrease serum calcium and PTH levels (Schnabel et al. 2014); k No reports of cinacalcet clinical use in these patients (Lam et al. 2005); ✕ indicates a drug had no effect on CaSR expression or signaling in this study; ...
Loss-of-function calcium-sensing receptor (CaSR) mutations cause the mineral metabolism disorders familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism,and increase the risk of femoral fracture, chronic kidney disease, coronary heart disease, and other diseases. In severe cases, CaSR mutations are lethal. Off-label use of the CaSR positive allosteric modulator (PAM), cinacalcet, corrects hypercalcemia in some patients with CaSR mutations. However, other patients remain unresponsive to cinacalcet, attesting to the need for novel treatments. Here we compared the effects of cinacalcet to two other clinically approved synthetic CaSR activators, evocalcet and etelcalcetide, as well as a novel PAM, 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (MIPS-VD-836-108) on clinically relevant CaSR mutations. We assessed the compounds in CaSR-expressing HEK293 cells for correction of mutation-induced impairments in intracellular calcium (Ca2+i) mobilization and cell surface expression. While cinacalcet, MIPS-VD-836-108 and evocalcet rescued the signaling of cell surface-expressed mutants, albeit to varying degrees, etelcalcetide was ineffective. Cinacalcet and evocalcet, but not MIPS-VD-836-108 or etelcalcetide, restored expression of a R680H mutant. However, no compound rescued expression of I81K and C582R mutants or a receptor missing 77 amino acids in the extracellular domain mimicking deletion of CASR exon 5, which impairs CaSR function. These data suggest specific compounds may be clinically effective in some patients with CaSR mutations, but other patients will remain refractory to treatment with currently available CaSR-targeting activators, highlighting the need for new generation drugs to rescue both the signaling and expression of mutant CaSRs.
... Both parents had calcium levels within the normal range and were unrelated, moreover the family history was unremarkable. NSHPT was confirmed by the finding of a previously reported heterozygous CaSR missense mutation at nucleotide position 554 (c.554G > A) in exon 4, leading to a substitution of arginine by glutamine at codon 185 [p.(Arg185Gln)] (14)(15)(16)(17). This mutation was absent in both parents indicating a de novo mutation. ...
... In NSHPT, treatment options include total or subtotal parathyroidectomy, infusions of bisphosphonates, intravenous hyper-hydration and diuretics (2,3,8). In the last years, cinacalcet, a positive allosteric activator of the CaSR, have been used in the management of NSHPT to increase the receptor's sensitivity to extracellular calcium (2,(14)(15)(16)(17)(20)(21)(22)(23)(24). The success of cinacalcet therapy in this clinical setting depends on the location of the mutation on the CaSR gene and the residual function of the mutated receptor (2,(14)(15)(16)(17)(20)(21)(22)(23)(24). ...
... In the last years, cinacalcet, a positive allosteric activator of the CaSR, have been used in the management of NSHPT to increase the receptor's sensitivity to extracellular calcium (2,(14)(15)(16)(17)(20)(21)(22)(23)(24). The success of cinacalcet therapy in this clinical setting depends on the location of the mutation on the CaSR gene and the residual function of the mutated receptor (2,(14)(15)(16)(17)(20)(21)(22)(23)(24). The p.(Arg185Gln) mutation is located in the extracellular domain of the CaSR and is associated with severe hypercalcemia and/or NSHPT even in a heterozygotic state, due to its dominant negative properties (25,26). ...
Background
In recent years, heterozygous loss-of-function mutations of the Calcium Sensing Receptor gene (CaSR) were implicated in different hypercalcemic syndromes besides familial hypocalciuric hypercalcemia (FHH), including neonatal severe primary hyperparathyroidism (NSHPT) and primary hyperparathyroidism (PHPT).
Cases presentation
Here we describe two unusual presentations of heterozygous inactivating CaSR mutations. Case 1: a case of NSHPT due to a de novo , p.(ArgR185Gln) CaSR mutation and successfully treated with cinacalcet monotherapy for 8 years until definitive surgical resolution. Case 2: a 37 years-old woman with PHPT complicated with hypercalcemia and nephrocalcinosis with a novel heterozygous p.(Pro393Arg) CaSR mutation and cured with parathyroidectomy.
Conclusions
These cases reinforce the fact that the clinical spectrum of inactivating mutations of the CaSR has widened and, although carrying a mutation suggestive of FHH, some patients may have different clinical phenotypes and complications requiring individualized therapies.
... Heterozygous loss-of-function CASR variants usually lead to FHH, whereas homozygous or compound heterozygous CASR variants result in NSHPT (Marx and Goltzman, 2019). However, pathogenic heterozygous loss-of-function CASR variants have also been described in some cases of NSHPT, notably the c.554G>A p.(Arg185Gln) missense pathogenic variant (Fisher et al., 2015;Reh et al., 2011;Forman et al., 2019;Gannon et al., 2014;Obermannova et al., 2009;Bai et al., 1997). ...
... We performed an exhaustive review of the literature using the PubMed database to compile clinical data on individuals with the same pathogenic variant, Arg185Gln in NSHPT and all descriptions of cinacalcet therapy in NSHPT (Table 1) (Pollak et al., 1993;Fisher et al., 2015;Reh et al., 2011;Forman et al., 2019;Gannon et al., 2014;Obermannova et al., 2009;Bai et al., 1997;Szalat et al., 2015;Heath et al., 1996) using the following terms: "NSHPT", "neonatal severe hyperparathyroidism", "R185Q", "p.(Arg185Gln)", "CASR", "CaSr", "CaSeR", "cinacalcet", and "calcimimetics". ...
... Interestingly, the association of short ribs and renal abnormality led to an initial diagnosis of Jeune syndrome in our patient. The same diagnosis was initially suspected in a male patient reported by Fisher et al. who presented at birth with global hypotonia, bell-shaped chest, and metaphyseal irregularities (Fisher et al., 2015). In this case, the patient was secondarily diagnosis with NSHPT at 11 months of age after further review of the radiographs revealed signs of metabolic bone disease (diffuse osteopenia, short ribs with irregular rib ends, and metaphyseal sclerosis at the ends of multiple long bones) and a biochemical evaluation indicated PTH-dependent hypercalcemia (Fisher et al., 2015). ...
Background
Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH.
NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs.
Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype.
Case presentation
We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful.
Discussion
An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.
