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Context: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy., Objective: The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1., Methods: A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent., Results: The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation., Conclusions: Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood., (© Endocrine Society 2020.)

Congenital hypomagnesemia is a rare disease, with an impact on cognitive and neurological development. We report on three familial cases of congenital hypomagnesemia, two boys and one girl who belong to the same consanguineous family. They all presented neonatal seizures and a psychomotor developmental delay. Cerebral computed tomography showed cerebral atrophy and calcifications in one case and magnetic resonance imaging found predominant cerebellar atrophy in the two other cases. All three patients also had hypocalcemia, hyperphosphoremia, and hypomagnesemia. The parathyroid hormone blood level was low in two cases and normal in the third. One 7-month old patient died. The others received a supplementation of calcium and magnesium, which normalized calcemia, phosphatemia but not magnesemia, which remained low despite high doses. They have both developed cognitive and behavioral impairments., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Neonatal seizures are a potentially life-threatening pediatric problem with a variety of causes, such as birth trauma, asphyxia, congenital anomalies, metabolic disturbances, infections, and drug withdrawal or intoxication. Thorough and timely evaluations of such patients are necessary to identify and treat the underlying etiology, therefore reducing potential morbidity and mortality. We review neonatal seizures and hypocalcemia and present the case of a 6-day-old male infant who presented to a tertiary pediatric emergency department with seizure-like episodes. He was found to have markedly low serum calcium, magnesium, and parathyroid hormone concentrations, as well as a significantly elevated serum phosphate concentration. The etiology of these abnormalities was found to be maternal ingestion of extremely high doses of calcium carbonate during the third trimester of her pregnancy, an occurrence that has been reported only once in the literature. Education pertaining to the dangers of excessive calcium carbonate intake during pregnancy may be an important piece of anticipatory guidance for pregnant mothers with symptoms of gastroesophageal reflux, and questioning the mother of a neonate presenting with seizures about such over-the-counter medications may help to elucidate the diagnosis.

Infantile malignant osteopetrosis (IMO; OMIM 259700) is a rare inherited bone disease characterized by reduced or dysregulated activity of osteoclasts, resulting in generalized osteosclerosis. The disease usually presents within the first few months of life with anemia, hepatosplenomegaly, frontal bossing, nystagmus, blindness, deafness, and bone fractures. Children with IMO are at risk of developing hypocalcemia, with attendant tetanic seizures. We report the case of a baby boy who presented with neonatal hypocalcemia. Skeletal radiographs demonstrated sclerotic bones and a dense base of the skull with typical "space alien" face confirming the diagnosis of IMO. Pancytopenia developed at 2 months of age. Visual evoked potential showed severe bilateral optic nerve damage. Genetic mutation study revealed a new mutation in exon 13 of the TCIRG1 gene. Neonatal hypocalcemia can occur as result of IMO, which is easily missed out by clinicians. This causes delay in establishing the diagnosis and starting necessary treatment. Therefore, osteopetrosis should be kept in mind as a rare cause of neonatal hypocalcemia.

Vitamin D has an important role in bone-metabolism (and its deficiency can cause preterm osteopenia, craniotabe and rickets), but it has also non-calcitropic functions. In fact, vitamin D deficiency is correlated to chronic kidney disease, respiratory infections, type 1 diabetes, psoriasis, Crohn disease and neonatal hypocalcemia. Because of the vitamin D deficiency is a global problem, its role as a drug is fundamental for the human health in all ages.

Objective: To characterize the endocrine and autoimmune disturbances with emphasis on parathyroid dysfunction in patients with 22q11.2 deletion syndrome (22q11.2 DS). Design In this nationwide survey; 59 patients (age 1-54 years) out of 86 invited with a 22q11.2 DS were recruited through all the genetic institutes in Norway., Methods: Data was collected from blood tests, medical records, a physical examination and a semi-structured interview. We registered autoimmune diseases and measured autoantibodies, hormone levels and HLA types., Results: Twenty-eight (47%) patients had hypoparathyroidism or a history of neonatal or transient hypocalcemia. Fifteen patients had neonatal hypocalcemia. Fourteen patients had permanent hypoparathyroidism including seven (54%) of those above age 15 years. A history of neonatal hypocalcemia did not predict later occurring hypoparathyroidism. Parathyroid hormone levels were generally low indicating a low reserve capacity. Twenty-eight patients were positive for autoantibodies. Six (10%) persons had developed an autoimmune disease, and all were females (P<0.02). Hypoparathyroidism correlated with autoimmune diseases (P<0.05), however, no antibodies were detected against the parathyroid glands., Conclusions: Hypoparathyroidism and autoimmunity occur frequently in the 22q11.2 DS. Neonatal hypocalcemia is not associated with later development of permanent hypoparathyroidism. Hypoparathyroidism may present at any age, also in adults, and warrants regular measurement of calcium levels. Hypoparathyroidism and autoimmunity occur frequently together. Our findings of autoimmune diseases in 10% of the patients highlight the importance of stringent screening and follow-up routines.

Primary hyperparathyroidism (PHP) during pregnancy is a very rare event that increases maternal and perinatal morbidity and mortality. We present a case in which hypocalcemic tetany of the neonatal infant - caused by transient hypoparathyroidism in the child - finally revealed asymptomatic maternal PHP. An apparently healthy 30-year-old woman had an uneventful pregnancy and delivery. On the 15th postpartal day, the newborn developed hypocalcemic tetany. After receiving supplementation of calcium and vitamin D, the child developed without further pathological findings. Laboratory and radiological studies in the mother led to a diagnosis of maternal PHP. An adenoma of the right lower parathyroid gland was subsequently removed. The search for the cause of hypocalcemia in a newborn should not focus on the patient alone. Examining the apparently healthy mother and approaching the case in a multidisciplinary fashion may benefit both the child and the mother.

Unlabelled: To define the molecular pathogenesis of severe postnatal hypocalcemia in monozygotic twin sisters, we sequenced their CaR gene and identified a missense mutation, K29E. Expression of the mutant receptor in vitro showed a marked increase in Ca2+ sensitivity explaining the observed phenotype. Additional mutagenesis studies lead us to speculate concerning a novel mechanism whereby the K29E mutation may lead to receptor activation., Introduction: Activating mutations of the Ca(2+)-sensing receptor (CaR) gene have been identified in subjects with autosomal dominant hypocalcemia. Study of such mutations has provided insight into the mechanism of activation of the CaR., Materials and Methods: We performed biochemical and molecular genetic studies on monozygotic twin sisters who presented with early postnatal hypocalcemia and on their unaffected sister and parents. Functional characterization of mutant CaRs transfected in HEK-293 cells included immunoblots to monitor protein expression and Ca2+ stimulation of phosphoinositide hydrolysis to measure Ca2+ sensitivity., Results: We identified a K29E missense mutation in the twin sisters but not in their parents or unaffected sister. The K29E mutant CaR showed a marked increase in Ca2+ sensitivity, including when it was co-transfected with wildtype CaR cDNA, consistent with a dominant effect. Substitution of K29 by aspartate equivalently increased CaR sensitivity, whereas conservative substitution by arginine did not., Conclusions: Severe postnatal hypocalcemia in the twin sisters was caused by a de novo germline activating mutation. In a model of the Venus flytrap-like domain of the extracellular amino-terminus of the CaR, K29 is located close to a peptide loop, "loop 2," that forms part of the dimer interface and is the site of 10 of the previously reported naturally occurring activating CaR mutations. We speculate that K29E increases Ca2+ sensitivity of the CaR by disrupting a salt bridge between K29 and an acidic residue in loop 2 and thereby changes the normal structure of loop 2 that maintains the CaR in its inactive conformation.

Gestational diabetes mellitus is a relatively common medical condition that was described as early as the nineteenth century. This article discusses the maternal and fetal pathophysiology and the impact of the maternal condition on the neonate. Fetal macrosomia and infant respiratory distress syndrome, cardiomyopathy, hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperviscosity all can occur as a result of maternal hyperglycemia and are discussed in detail. Therapeutic approaches and treatment options for the mother, manifestations and diagnosis of the infant, and current research related to this condition are also included.

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency present with a Reye-like syndrome, cardiomyopathy, or sudden unexpected death. We describe an unusual presentation in a patient with unsuspected LCHAD deficiency. The proband presented at 2 months of age with an acute infantile hypocalcaemia and vitamin D deficiency associated with occult, unexplained cholestatic liver disease. Sudden, unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the prevalent LCHAD (1528G > C, E474Q) mutation. The mother had pre-eclampsia during the third trimester of her pregnancy. In a subsequent pregnancy, she developed severe acute fatty liver of pregnancy (AFLP) and intrauterine fetal death at 33 weeks of gestation. In conclusion, infantile hypocalcaemia is an unusual phenotype associated with LCHAD deficiency. The maternal pregnancy history documents that fetal LCHAD deficiency is associated with a spectrum of maternal illnesses ranging from pre-eclampsia to life-threatening AFLP.

Objective: To study the usefulness of fluorescent in situ hybridization (FISH) with the DNA probe D22S75 for detecting microdeletions in chromosome 22q11.2 in metaphases from patients with features of "CATCH 22" (cardiac anomalies, abnormal facies, thymic hypoplasia or aplasia, cleft palate, and hypocalcemia)., Methods: High-resolution chromosome analysis and FISH were performed on metaphases from 10 control subjects, 42 patients with features of CATCH 22, and 6 parents of children with CATCH 22. Patients were screened for conotruncal heart defect, palatal abnormality, and facial features. We correlated the phenotype, karyotype, and deletion of a D22S75 locus., Results: Specimens from nine patients with one or more features of CATCH 22 had a single hybridization signal for D22S75, indicating a deletion of chromosome 22q11.2. Four patients had all the major features of the syndrome and a chromosomal deletion. Thirteen patients had two CATCH 22 features, five of whom had a deletion. None of the 25 patients with a single CATCH 22 feature had a deletion. One patient with a deletion detected by FISH also had a deletion noted on high-resolution banding. All six parents who had blood samples studied by FISH had normal hybridization patterns., Conclusion: FISH is a useful adjunct to chromosome analysis for assessing patients with features of CATCH 22. Detecting a chromosomal deletion by FISH provides a definitive diagnosis and helps to ensure appropriate medical management and genetic counseling.

We report repair of anomalous origin of the right pulmonary artery from the ascending aorta in a premature neonate with a deletion in the CATCH 22 region of chromosome 22. This case suggests that the pathogenesis of anomalous origin of the right pulmonary artery involves genetically determined abnormalities of the neural crest. Repair of this defect in a premature infant can prevent the development of severe pulmonary vascular disease.

The authors present a case of enormous neonatal ovarian cyst associated with ipoglicemia, ipotiroidism and ipocalcemia. This baby presents also stenosis of the pulmonary artery and congenital dysplasia of the hip. The case is interesting because this type of association is unusual and has not been described before.

Primary hyperparathyroidism in the mother during pregnancy is known to result in a high rate of fetal complications; spontaneous abortions, still births, and neonatal tetany occur in excessive incidence. To understand the pathophysiology of neonatal hypocalcemia that accompanies this disorder, transplacental calcium dynamics were studied in female sheep during the last trimester of pregnancy and in their fetal lambs after hysterotomy. Calcium ion was shown to move rapidly across the placenta. However, this organ blocked the passage of both parathyroid hormone and calcitonin from the maternal and to the fetal circulations. Our studies support the hypothesis that in primary hyperparathyroidism maternal hypercalcemia results in fetal hypercalcemia, which leads to suppression of fetal parathyroid gland function. In such a situation, neonatal hypocalcemia would occur after birth when maternal calcium flow is interrupted. Parathyroidectomy performed in the mother, especially during the second trimester of pregnancy when operation is safest, would break this cycle and permit normal serum calcium homeostasis in the fetus.

Although relatively uncommon, the conditions of hypoparathyroidism and pseudohypoparathyroidism in childhood provide an exciting diagnostic and therapeutic challenge. Knowledge of calcium-phosphate homeostasis has progressed rapidly over the past few years so that our understanding of the basic pathophysiological mechanisms has increased tremendously. However, further clinical and basic scientific research will, no doubt, unravel further variations of the various disease entities described.

Calcium metabolism in pregnancy is a complex process involving calcium, phosphorus, vitamin D, parathyroid hormone (PTH), and calcitonin (CT). Calcium absorption is enhanced in pregnancy, and increased storage in the maternal skeleton probably occurs as well. Adequate amounts are provided by the current Recommended Dietary Allowance of 1,200 mg. daily which can be met readily by natural foods, specifically milk. If supplemental calcium is given, a nonphosphate salt is probably advisable, since some evidence suggests that excessive phosphate intake may be related to leg cramps in pregnancy. Vitamin D is necessary for optimal calcium utilization in pregnancy, although the possibility of fetal toxicity with overdosage has been suggested. From a review of available information with respect to maternal-perinatal calcium interrelationships, I propose the following hypothesis: While total maternal serum calcium declines during pregnancy because of the physiologic hypoalbuminemia, the level of ionic calcium remains constant, in part, at least, because of increasing maternal PTH output. The placenta plays a primary role in fetal calcium metabolism by transporting calcium ions from the mother to the fetus against a concentration gradient. Relatively high fetal ionic calcium levels cause suppression of PTH and stimulation of CT in the fetus, facilitating growth of the fetal skeleton. With sudden loss of the placental source of calcium at birth, the newborn infant becomes functionally hypoparathyroid and/or hypercalcitonemic, and the serum calcium level declines until 3 to 4 days of life when PTH rises and CT falls with a resultant slight rise in calcium.

Thirty-three observations of late-onset neonatal hypocalcemia were reviewed retrospectively. Their etiological, clinical and biological features were consistent with a transient congenital hypoparathyroidism, associated with a materno-foetal vitamin D deficiency. 1 alpha-hydroxycholecalciferol was used for rapid correction of calcemia and proved to be satisfactorily metabolized after its oral administration.

The authors report the case of dizygotic twins suffering from transitory neonatal hypoparathyroidy and leading to the diagnosis of maternal hyperparathyroidy. The differences of clinical and biological symptomatology between these twins suggest individual variations in response to phosphocalcic disorders of the mother. A review of literature find 31 other cases. This study emphasize the aggravation by the mild hypomagnesemia frequently associated, the usual severity of initial clinical symptomatology in contrast with a good neurologic outcome, the diagnosis of maternal hyperparathyroidy.

Serum parathyroid hormone and total and ionized Ca, Mg, and P levels were determined serially from birth to 96 hr of age in 28 infants of diabetic mothers (IDM, 15 Class A, 13 Class B, C, D) and their respective mothers at the time of delivery. In spite of marked decreases in concentrations of serum total and ionized Ca from birth to 24 to 48 hr, there was an insignificant increase in serum PTH values over this period in infants of insulin-dependent mothers. Infants of Class A diabetic mothers had an equivocal PTH response. Nineteen term control infants were similarly examined and had a significant increase in serum PTH postnatally. Relatively higher values of serum ionized Ca at birth in IDM were followed by greater decreases in ionized Ca from birth to 24-48 hr of age, and by decreased neonatal parathyroid function. The data support functional hypoparathyroidism as a basis for the hypocalcemia and hyperphosphatemia of IDM. It is speculated that increased concentrations of serum ionized Ca in utero and suppression of activity in the fetal parathyroid glands may be a cause for the functional hypoparathyroidism.

The aetiological factors in enamel defects of a non-fluoride nature can be divided into systemic and local. The systemic factors comprise a variety of conditions: genetically determined, chromosomal anomalies, congenital defects, inborn errors of metabolism, neonatal disturbances, infectious diseases, neurological disturbances, endocrinopathies, nutritional deficiencies, nephropathies, enteropathies, liver diseases and intoxications. The genetically determined enamel defects include amelogenesis imperfecta, which may occur as an isolated phenomenon or as part of other disorders such as epidermolysis bullosa, pseudohypoparathyroidism and taurodontism. The congenital defects include heart disorders and unilateral facial hypoplasia and hypertrophy. Among the inborn errors of metabolism are: galactosaemia, phenylketonuria, alkaptonuria, erythropoietic porphyria and primary hyperoxaluria. Neonatal disturbances are important in the development of enamel hypoplasia, foremost among these are premature birth and hypocalcaemia. The latter causes postnatal hypoplasias, which, however, are never seen in breast-fed children. Haemolytic anaemia, mostly in conjunction with erythroblastosis foetalis, may cause enamel hypoplasia. In children with neurological disturbances a rather large number have enamel hypoplasias, and these changes may be a significant aid in neurological diagnosis. When the tetracyclines were introduced, many children had these drugs prescribed in the period when the teeth were undergoing mineralization. The result was a yellow-brown stain of the affected teeth. In recent years, however, there appears to have been a reduction in the incidence of tetracycline staining. As for local causes the most important are traumatic injuries and periapical osteitis of primary teeth.