GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

One half-century of advances in the evaluation and management of disorders of bone and mineral metabolism in children and adolescents.

The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that affect the developing skeleton. Progress has been facilitated through advances in both technology and biology and this paper provides a brief description of some but not all of the key findings, including identification of the calcium sensing receptor and the polypeptides parathyroid hormone and parathyroid hormone-related protein as well as their shared receptor and signal generating pathways; the elucidation of vitamin D metabolism and actions; discovery of fibroblast growth factor 23 (FGF23), the sodium-phosphate co-transporters and the other components that regulate phosphate metabolism. Moreover, the past half-century of research has led to the delineation of the molecular bases for genetic forms of hypoparathyroidism, pseudohypoparathyroidism, and primary hyperparathyroidism as well as the determination of the genetic causes of osteogenesis imperfecta, osteopetrosis, hypophosphatasia, and other disorders of mineral/bone homeostasis. During the next decade we expect that many of these fundamental discoveries will lead to the development of innovative treatments that will improve the lives of children with these disorders.

Congenital absence of norepinephrine due to CYB561 mutations.

OBJECTIVE: Cytochrome b561 (CYB561) generates ascorbic acid, a cofactor in the enzymatic conversion of dopamine to norepinephrine by dopamine ß-hydroxylase. We propose that the clinical relevance of this pathway can be revealed by characterizing the autonomic and biochemical characteristics of patients with CYB561 mutations. METHODS: We performed autonomic evaluations in 4 patients with lifelong orthostatic hypotension in whom CYB561 mutations were determined by genomic sequencing. RESULTS: Patients had disabling lifelong orthostatic hypotension (OH) and impaired blood pressure response to the Valsalva maneuver (VM), with exaggerated hypotension during phase 2 and lack of overshoot during phase 4. Heart rate ratios for sinus arrhythmia and the VM were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine levels and improved OH. Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a missense mutation in exon 2, c157C>T, p.His.53Tyr, and the other had an exon 2 deletion. CONCLUSION: CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. We report a novel case of CYB561 deficiency due to an exon 2 deletion in one allele and a missense mutation in the other. These patients highlight the critical role CYB561 plays in sympathetic function and cardiovascular regulation.

A novel CASR mutation associated with neonatal severe hyperparathyroidism transmitted as an autosomal recessive disorder.

BACKGROUND: Neonatal severe primary hyperparathyroidism (NSHPT, MIM 239200) is most often an isolated disorder that is due to biallelic inactivating mutations in the CASR, the gene encoding the calcium sensing receptor; NSHPT is inherited from parents with familial hypocalciuric hypercalcemia, each of whom has one mutated CASR allele. OBJECTIVES: To report clinical and genetic findings in a brother and sister with NSHPT due to a novel mutation in the CASR transmitted as an autosomal recessive trait and to examine the functional effect of the mutation. SUBJECTS AND METHODS: A brother and sister with marked hypercalcemia due to NSHPT were identified; the boy also had craniosynostosis requiring surgical repair. The genotyping of the CASR in both children and their parents who were eucalcemic and normophosphatemic was undertaken. In order to examine the significance of the variant CASR identified, the CASR variant was expressed in vitro and examined by three computer computational programs [PolyPhen2, MutationTaster, Sorting Intolerant From Tolerant (SIFT)] designed to evaluate the effect of a nucleotide variant on the structure and likely functional consequence upon the protein product. RESULTS: A sequence variant in the CASR was identified [G>T point mutation at nucleotide c.2303 in exon 7 (c.2303G>T) resulting in the replacement of glycine by valine at codon 768 (p.Gly768Val)]. Two copies of this CASR variant were present in the genome of the siblings while a single copy of the CASR variant was present in both of the clinically and biochemically normal parents, a pattern of transmission consistent with autosomal recessive inheritance of NSHPT in this family. When expressed in HEK293 cells in vitro, the novel Gly768Val variant did not interfere with protein generation or migration to the cell membrane in vitro. The analysis of the functional effect of the Gly768Val CASR variant by the PolyPhen2, MutationTaster, and Sorting Intolerant From Tolerant computer programs revealed that this mutation was very likely to be deleterious. CONCLUSION: The NSHPT associated with biallelic Gly768Val mutations of the CASR in two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.

Disorders of aldosterone synthesis, secretion, and cellular function.

PURPOSE OF REVIEW: The purpose of this review is to describe the renin-angiotensin-aldosterone system and its regulatory control of sodium, potassium, chloride, hydrogen ion, and water homeostasis through its effects on the expression and activity of distal renal tubular cotransporter proteins and to discuss the gene mutations encoding these structures that disturb the function of this system. RECENT FINDINGS: Primary hypoaldosteronism may be the result of acquired or congenital errors in renal juxtaglomerular function (the source of renin), angiotensin generation or activity, or aldosterone synthesis. Secondary hypoaldosteronism (pseudohypoaldosteronism) occurs as a consequence of mutations in genes encoding the mineralocorticoid receptor (MR), the three subunits of the aldosterone-responsive, amiloride-sensitive nonvoltage-gated sodium channel encoded by SCNN1A, SCNN1B, and SCNN1G, the gene that regulates posttranslational phosphorylation (encoded by WNK4) of the thiazide-sensitive sodium chloride cotransporter encoded by SLC12A3, and those that regulate phosphorylation and ubiquitination of cofactors encoded by WNK1, KLH3, and CUL3 that affect WNK4 function. SUMMARY: Acquired disorders of renal function as well as mutations in many genes may adversely affect aldosterone-mediated mineral homeostasis.

Empty sella syndrome.

An empty sella (ES) develops when cerebrospinal fluid (CSF) fills the sella turcica and compresses pituitary tissue until it lines the sellar floor and walls. Primary ES occurs when CSF enters the sella through a rent in the sellar diaphragm that may or may not be associated with increased intracranial pressure. Secondary ES is a result of an injury to the pituitary itself (e.g., pituitary apoplexy) or the consequence of surgical or radiation treatment. In adults, ES is most commonly found in older, obese, hypertensive, multiparous women and may be asymptomatic. In children, however, ES is more likely to be associated with clinical symptoms and endocrinopathies, particularly growth hormone deficiency, hypogonadotropism, or multiple pituitary hormone deficiencies. The incidence of ES in children varies greatly depending on the population surveyed, ranging from 1.2% (children without endocrine symptoms) to 68% (children with known endocrinopathy). Children with a finding of ES require endocrinologic and ophthalmologic evaluation. Treatment of ES includes replacement of hormone deficiencies and occasionally surgical measures to relieve obstructive intracranial lesions.

Gender related differences in glucocorticoid therapy and growth outcomes among pubertal children with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH).

Twenty-one-hydroxylase deficient congenital adrenal hyperplasia (CAH) causes glucocorticoid and mineralocorticoid deficiency, hyperandrogenism and short stature. Management of the pubertal CAH patient is particularly challenging. The purpose of this retrospective chart review study was to determine if pubertal males and females with simple virilizing CAH (SVCAH) required different glucocorticoid dosages at progressive Tanner stages. The relationship between hydrocortisone dose and height was also assessed. Twenty females and seventeen males with SVCAH were identified and followed throughout all stages of pubertal development. Males received an average hydrocortisone dose of 16.4±4.8 mg/m2/day and for females, 13.7±4.6 mg/m2/day. The glucocorticoid dosage in males was significantly higher than in females at Tanner stages 3 through 5. Higher doses were associated with a shorter (9.6 cm) achieved than anticipated adult height.

Treatment of growth hormone-deficient infants with recombinant human growth hormone to near-adult height: patterns of growth.

BACKGROUND/AIMS: To determine adult statures and linear growth patterns of children with growth hormone deficiency (GHD) who began treatment with recombinant human growth hormone (rhGH) in infancy. METHODS: Forty-seven patients with GHD in whom administration of rhGH was initiated at or before 2 years of age and who had achieved near-adult heights (NAH) were identified in the database of the Genentech National Cooperative Growth Study. RESULTS: After beginning treatment at a mean age of 0.9 years and height of -2.3 SD, these subjects achieved mean statures of -0.6, -0.3, and -0.4 SD at 5 and 10 years of age and at NAH, respectively. In 23 patients whose parental heights were known, mean NAH was comparable to the target height. Patients with uncomplicated courses whose heights were normal or tall when spontaneous puberty occurred or was induced realized the tallest NAHs. Patients with severe prenatal or perinatal, congenital and acquired neurologic insults, sexual precocity, or associated illnesses achieved less optimal NAHs. CONCLUSION: A normal pattern of linear growth during childhood and adolescence and satisfactory NAHs can be achieved in the majority of patients when treatment of the GHD subject is begun during infancy.