Collagen X Marker Levels are Decreased in Individuals with Achondroplasia.

Collagen X marker (CXM) is a degradation fragment of collagen type X. It is a real-time biomarker of height velocity with established norms. Plasma C-type natriuretic peptide (CNP) and NTproCNP levels have also been found to correlate with growth velocity in the general population and are elevated in individuals with achondroplasia compared with age- and sex-matched controls.

Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions.

Context: Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications.

Objective: This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally.

Norms for Clinical Use of CXM, a Real-Time Marker of Height Velocity.

Context: Height velocity (HV) is difficult to assess because growth is very slow. The current practice of calculating it from measurements taken at several-month intervals is insufficient for managing children with growth disorders. We identified a bone growth by-product (collagen X biomarker, CXM) in blood that in preliminary analysis in healthy children correlated strongly with conventionally determined HV and displayed a pattern resembling published norms for HV vs age.

Pitfalls with Vitamin D Research in Musculoskeletal Disorders and Recommendations on How to Avoid Them.

Reports suggesting that vitamin D may have extraskeletal roles have renewed interest in vitamin D research and stimulated publication of an increasing number of new studies each year. These studies typically assess vitamin D status by measuring the blood concentration of 25-hydroxyvitamin D [25(OH)D], the principal circulating metabolite of vitamin D. Unfortunately, variations in assay format, inconsistency in interpreting 25(OH)D concentrations, cohort bias (age, body mass index, race, season of measurements etc.

Dynamic response of C-type natriuretic peptide and its aminoterminal propeptide (NTproCNP) to growth hormone treatment in children with short stature.

Objective: C-type natriuretic peptide (CNP) and its aminoterminal propeptide (NTproCNP) are potential biomarkers of recombinant human growth hormone (rhGH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTproCNP levels in response to rhGH treatment and to identify the optimal time of sampling after starting rhGH.

Design: This was a prospective, observational study.

Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature.

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family.

C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia.

Context: C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In a previous report of a child with acromesomelic dysplasia, Maroteaux type (AMDM), caused by loss-of-function of the CNP receptor (natriuretic peptide receptor-B [NPR-B]), plasma levels of CNP were elevated. In vitro studies have shown that activation of the MAPK kinase (MEK)/ERK MAPK pathway causes functional inhibition of NPR-B.

Acute inflammation in young children inhibits C-type natriuretic peptide.

Background: C-type natriuretic peptide (CNP) is a paracrine growth factor critical in endochondral bone growth. Amino-terminal CNP (NTproCNP), measurable in plasma, correlates with growth-plate activity and can be used as a biomarker of growth velocity in children. Because severe inflammation in adults increases CNP, we studied CNP peptides and inflammatory markers in children with acute illness.

C-Type Natriuretic Peptide (CNP) levels are altered in boys with Klinefelter syndrome.

Context: B-type natriuretic peptide (BNP) expression in vitro is up-regulated by the protein coded by the short stature homeobox gene (SHOX). C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate that plays a key role in endochondral growth and shares clearance pathways with BNP. We explored the possibility that alterations in natriuretic peptide regulation may play a role in the overgrowth of boys with Klinefelter syndrome.

Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children.

Objective: C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino-terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children.

C-type natriuretic peptide forms in adult hyperthyroidism: correlation with thyroid hormones and markers of bone turnover.

Context: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown.

Mechanisms of impaired growth: effect of steroids on bone and cartilage.

Background: Long-term treatment with high-dose glucocorticoids (GCs) has profound effects on bone metabolism and linear growth. Bone metabolism is a balance between bone resorption by osteoclasts and new bone formation by osteoblasts. Systemically, GC treatment reduces circulating levels of estrogen and modestly increases parathyroid hormone levels.

Healthy children with frequent fractures: how much evaluation is needed?

Objective: We performed a case-control study to determine whether occult bone disease is associated with a history of frequent fractures in children.

Methods: Healthy children with > or = 2 incidences of low-energy fractures were recruited (n = 68). Children with no history of fractures served as control subjects (n = 57).

Amino-terminal propeptide of C-type natriuretic peptide and linear growth in children: effects of puberty, testosterone, and growth hormone.

Context: C-type natriuretic peptide (CNP), a paracrine factor of the growth plate, plays a key role in stimulating bone growth. The amino-terminal propeptide of CNP (NTproCNP) is produced in equimolar amounts with CNP and is measurable in plasma, providing a potential biomarker for growth plate activity and, hence, linear growth.

Objective: We explored the effects of puberty, testosterone, and GH treatment on NTproCNP levels in normal and short-statured children.

C-type natriuretic peptide in growth: a new paradigm.

C-type natriuretic peptide (CNP), acting through its receptor, natriuretic peptide receptor-B (NPR-B), plays a critical role in linear growth. Knockout mice for CNP and NPR-B are dwarfed, and transgenic mice overexpressing CNP are overgrown. CNP has a direct regulatory effect on growth plate chondrocytes, acting primarily to promote terminal differentiation and hypertrophy.

Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature.

Context: C-type natriuretic peptide (CNP) is an important regulator of skeletal growth. Loss-of-function mutations affecting the CNP receptor natriuretic peptide receptor-B (gene NPR2) cause the autosomal recessive skeletal dysplasia, acromesomelic dysplasia, Maroteaux type (AMDM). The phenotype of heterozygous carriers of NPR2 mutations is less clear.

A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.

A unique heterozygous 3-kb microdeletion within STX16, a closely linked gene centromeric of GNAS, was previously identified in multiple unrelated kindreds as a cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib). We now report a novel heterozygous 4.4-kb microdeletion in a large kindred with AD-PHP-Ib.

Growth factor regulation of human growth plate chondrocyte proliferation in vitro.

Linear growth occurs as the result of growth plate chondrocytes undergoing proliferative and hypertrophic phases. Paracrine feedback loops that regulate the entry of chondrocytes into the hypertrophic phase have been shown and similar pathways likely exist for the proliferative phase. Human long-bone growth plate chondrocytes were cultured in vitro.

Regulation of bone mass by growth hormone.

Growth hormone (GH) is a peptide hormone secreted from the pituitary gland under the control of the hypothalamus. It has a many actions in the body, including regulating a number of metabolic pathways. Some, but not all, of its effects are mediated through insulin-like growth factor-I (IGF-I).

Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males.

Objective: This report describes a new fatal syndrome observed in adolescent males at the initial presentation of diabetes mellitus. The features include hyperglycemic hyperosmolar coma complicated by a malignant hyperthermia-like picture with fever, rhabdomyolysis, and severe cardiovascular instability.

Design: Case series.

Using real-time, quantitative PCR for rapid genotyping of the steroid 21-hydroxylase gene in a north Florida population.

The most common cause of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency. The molecular genetics of this disease are such that genotyping is a potentially useful tool in its diagnosis. An assay was developed using real-time, quantitative PCR to detect deletions of the steroid 21-hydroxylase gene (CYP21A2).