Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

Kenny-Caffey Syndrome Type 2: A Unique Presentation and Craniofacial Analysis.

Kenny-Caffey Syndrome Type 2 (KCS2) is a rare genetic disorder characterized by short stature, skeletal dysplasia, primary hypoparathyroidism, and delayed closure of the anterior fontanelle. Patients with KCS2 typically require multidisciplinary management due to numerous craniofacial and skeletal anomalies. Craniosynostosis, however, has not yet been identified in a patient with KCS2 to the best of our knowledge. We present the first case of craniosynostosis in the setting of KCS2 and provide a comprehensive analysis of the associated craniofacial findings to date. The authors will describe the craniofacial features specific to our patient and review the characteristic morphological features in a manner relevant to early recognition and focused evaluation.

Effect of baseline hypocalcaemia on volume of intracerebral haemorrhage in patients presenting within 72 hours from symptom onset.

INTRODUCTION: Calcium has a pivotal role in haemostasis. We investigated the association of baseline calcium levels with admission intracerebral haemorrhage (ICH) volume. METHODS: This is a retrospective analysis of consecutive ICH patients in an academic hospital between January 2005 and March 2010. Computed tomography (CT) of the brain and serum/plasma ionized calcium had to be taken within 72 h of symptom onset and within 12 h of each other in order to fulfil the study criteria. ICH cases related to trauma or tumour as well as sole intraventricular haemorrhages were excluded. Baseline haematoma volumes were calculated using semiautomated planimetry. The hypocalcaemic (Ca-ion <1.16 mmol/L) and normocalcaemic (1.16-1.30 mmol/L) patient groups were compared in univariate analyses. Association between admission hypocalcaemia and haematoma volume was studied using multivariable regression models. RESULTS: Out of 1013 consecutive patients, 447 fulfilled the study criteria. Hypocalcaemic patients (n = 178; 39.8%) had larger baseline hematoma volumes (median 30.2 mL, IQR 11.4-58.7 mL), compared to normocalcaemic patients (n = 255; 57.0%; median 16.8 mL, IQR 7.4-44.2 mL). The median ICH volume among hypercalcaemic patients (n = 14; 3.1% of included patients) was 6.5 mL (IQR 3.1-34.6 mL). On linear regression, admission hypocalcaemia was independently associated with larger hematoma volumes (ß = 11.77; 95% CI 4.66-18.87, P = 0.01). Patients with larger haematoma volumes had higher mortality. CONCLUSION: Hypocalcaemia is associated with larger admission haematoma volumes among ICH patients. Higher mortality among hypocalcaemic patients is very likely mediated through larger ICH volumes.

Bone Status Among Patients With Nonsurgical Hypoparathyroidism, Autosomal Dominant Hypocalcaemia, and Pseudohypoparathyroidism: A Cohort Study.

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research.

Severe Hypocalcemia in a Patient with Recurrent Chondrosarcoma.

Hypocalcemia is relatively uncommon paraneoplastic syndrome. Only one case of hypocalcemia has been reported in a patient with chondrosarcoma. We herein report a case of a 32-year-old woman with metastatic chondrosarcoma with tetany. Her imaging findings revealed multiple calcific metastatic lesions in the lungs, pancreas, left atrium, and pulmonary vein. A laboratory examination showed hypocalcemia with no evidence of any other disease that could induce hypocalcemia. On the basis of the laboratory and clinical findings, we concluded the etiology of her severe hypocalcemia to be excessive calcium consumption by the tumor itself.

Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. DESIGN: A three-generation family with seven members (3 adults, 4 children) presenting with ADH. METHODS: Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. RESULTS: Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children). CONCLUSIONS: The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

The effect of metritis and subclinical hypocalcemia on uterine involution in dairy cows evaluated by sonomicrometry.

The objective of this study was to examine the effects of metritis and subclinical hypocalcemia on reduction of uterine size in dairy cows using ultrasonography and sonomicrometry. Four piezoelectric crystals were implanted via laparotomy into the myometrium of the pregnant uterine horn of 12 pluriparous Holstein Friesian cows 3 weeks before the calculated calving date. Sonometric measurements were conducted daily from 2 days before parturition (= Day 0) until Day 14 after calving and then every other day until Day 28. Distances between adjacent crystals were expressed in relation to reference values obtained before calving. The diameter of the formerly pregnant uterine horn was measured using transrectal B-Mode sonography starting on Day 10. Cows were retrospectively divided into the following groups: cows without metritis (M-; n = 7), cows with metritis (M+; n = 5), cows with normocalcemia (SH-; Ca > 2.0 mmol/l on Days 1 to 3; n = 5) and cows with subclinical hypocalcemia (SH+; Ca < 2.0 mmol/l in at least one sample between Days 1 and 3; n = 7). Metritis did not affect (P > 0.05) sonometric measurements, but the diameter of the formerly pregnant horn was larger (P ≤ 0.05) between Days 15 and 21 in M+ cows than in M‒ cows. Reduction in uterine length in hypocalcemic cows was delayed (P ≤ 0.05) between Days 8 and 21 compared with normocalcemic cows, but the uterine horn diameter was not related to calcium status. In conclusion, both diseases affected reduction of uterine size until Day 28. Cows with metritis had a larger uterine diameter, possibly attributable to accumulation of lochia, and cows with subclinical hypocalcemia had delayed reduction of uterine length, presumably related to reduction of myometrial contractility.

Bone density assessment in a cohort of pediatric patients affected by 22q11DS.

OBJECTIVE: Hypoparathyroidism and hypocalcemia are two of the most frequent clinical characteristics of 22q11-deletion syndrome (22q11DS). The aim of this study was to evaluate bone metabolism and density in a cohort of patients affected by 22q11DS. METHODS: In 8 pediatric patients (mean age 11.5 years; range 7-16.4) affected by 22q11DS, creatinine, albumin, total and ionized calcium, phosphate, 25(OH) vitamin D, parathyroid hormone, osteocalcin, C-terminal telopeptide and interleukin 6 were assessed. Furthermore, bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry procedure. 14 healthy children were considered as controls. RESULTS: Most of the studied subjects were overweight and lacked quality physical activity. 40 % of the subjects had reduced calcium levels in the absence of related clinical symptoms and all patients also had inadequate levels of Vitamin D. The values of L1-L4 BMD were within the reference range in all patients (z score <2). However, after comparing the age-matched indexes of bone mineralization of patients with those of controls, the former had lower bone mineralization indexes than the latter. CONCLUSIONS: In pediatric patients with 22q11DS, an initial and slight bone loss is evident. The incidence of hypocalcemia is underestimated because hypocalcemia is asymptomatic. Several factors contribute to bone impairment in children who still have to achieve bone mass peak. Therefore, we suggest strict monitoring of bone metabolism as well as BMD measurement in patients affected by 22q11DS.

Severe resistant hypocalcemia in multiple myeloma after zoledronic acid administration: a case report.

INTRODUCTION: Hypercalcemia is one of the most common metabolic abnormalities encountered in any form of malignancy. Hypocalcemia, however, is a rare manifestation, especially in cancers with bone involvement. Here we present a case of hypocalcemia in a patient with multiple myeloma that was refractory to treatment. CASE PRESENTATION: A 73-year-old African American woman recently diagnosed with multiple myeloma, presented with a 2-day history of fever, vomiting and hypocalcemia. Ten days prior to admission she received zoledronic acid, Velcade® (bortezomib), Revlimid® (lenalidomide) and dexamethasone. Treatment was started with intravenous antibiotics and calcium gluconate boluses. After 24 hours of treatment her calcium level became undetectable (<5mg/dL). Continuous intravenous calcium gluconate infusions in addition to boluses were started. She remained persistently hypocalcemic and eventually developed tonic-clonic seizures. Vitamin D levels were found to be low and intravenous paricalcitol was initiated, which improved her calcium level. CONCLUSIONS: Underlying vitamin D deficiency can precipitate severe hypocalcemia in patients with multiple myeloma receiving bisphosphonates. This warrants baseline screening for vitamin D deficiency in these patients.

Hyperparathyroidism and hungry bone syndrome revisited.

A 36-year-old woman presented with a calcium level of 15.7 mg/dL (normal, 8.5-11.0 mg/dL) and an extremely elevated parathyroid hormone level of 1549.6 pg/mL (normal, 10.0-65.0 pg/ mL). She subsequently underwent a parathyroid scan and ultrasound evaluation, which suggested parathyroid carcinoma. Biopsy of a lytic lesion in her left iliac bone was performed because of concern for metastatic disease but revealed a brown tumor. The patient then underwent parathyroidectomy. The patient's postsurgical course was complicated by protracted symptomatic hypocalcemia consistent with hungry bone syndrome.

FAM111A mutations result in hypoparathyroidism and impaired skeletal development.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.

Symptomatic intracranial hypertension and prolonged hypocalcemia following treatment of Paget's disease of the skull with zoledronic acid.

Skull involvement in Paget's disease of bone can lead to neurological symptoms, prompting treatment. Intravenous zoledronic acid (ZA) has emerged as an effective and safe treatment option for patients with Paget's, leading to sustained remission and improved quality of life. A previously untreated 61-year-old female presented with 2-year history of facial asymmetry with progressive hearing impairment. Serum calcium levels were normal with upper normal levels of PTH and low 25OHD levels. Serum alkaline phosphatase was markedly increased and bone scan showed extensive pagetic involvement of the skull. Head CT and MRI revealed hydrocephalus with cerebellar tonsillar herniation, platybasia and basilar invagination. In the absence of clinical signs or symptoms of intracranial hypertension, she was treated with intravenous ZA after 15-day supplementation with calcium and vitamin D. Twelve hours after the infusion, the patient became confused, agitated and disoriented and developed urinary incontinence; cortical sulci became effaced on CT indicating increased intracranial pressure. Over the following days, she developed frank hypocalcemia requiring intravenous calcium infusion and calcitriol. Neurological status returned to normal within 24 h of onset, except for urinary incontinence. Nine months later she remained incontinent and still required calcitriol to maintain normocalcemia. Zoledronic acid is a first-line option for the treatment of Paget's disease, yet there can be complications in particular clinical scenarios such as pagetic hydrocephalus, as seen in this case. Plentiful supplementation of calcium and vitamin D before bisphosphonate therapy is paramount in order to minimize the risk of prolonged post-treatment hypocalcemia.

Oral manifestations of patients with Kenny-Caffey Syndrome.

Kenny-Caffey syndrome (KCS) is a rare osteosclerotic bone dysplasia characterized by hypocalcemia, short stature, ophthalmological features, and teeth anomalies. The TBCE gene coding for a tubulin-specific chaperone E, is located at chromosome 1q42-q43, and is responsible for the recessive form. After reviewing the literature, we found around 60 cases, however with limited dental data. In this article 5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showed dental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS, further study is required to better delineate the syndrome.