Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.

Introduction: Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases.

Adult Height of Patients with SHOX Haploinsufficiency with or without GH Therapy: A Real-World Single-Center Study.

Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height (AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRH analog (GnRHa).

Hormone resistance and short stature: A journey through the pathways of hormone signaling.

Hormone resistances have been described in association with growth disorders, the majority involving the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis or hormones with specific paracrine-autocrine actions in the growth plate. Defects in hormone receptors or in proteins involved in intracellular signal transduction (post-receptor defects) are the main mechanisms of hormone resistance leading to short stature. The characteristic phenotypes of each of these hormonal resistances are very distinct and bring with them important insights into the role of each hormone and its signaling pathway.

A Bayesian Approach to Diagnose Growth Hormone Deficiency in Children: Insulin-Like Growth Factor Type 1 Is Valuable for Screening and IGF-Binding Protein Type 3 for Confirmation.

Background: The utility of insulin-like growth factor type 1 (IGF-1) is well established in the diagnosis of growth hormone deficiency (GHD), whereas IGF-binding protein type 3 (IGFBP-3) has a more controversial role. Most studies evaluated the value of these peptides by assessing their sensitivity and specificity but not considering the low prevalence of GHD among short children (<2%).

Objective: To evaluate the utility of basal IGF-1 and IGFBP-3 values in the GHD diagnosis process with a Bayesian approach, based on pre- and post-test probability.

Update on new GH-IGF axis genetic defects.

The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade.

Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood.

Growth and Clinical Characteristics of Children with Floating-Harbor Syndrome: Analysis of Current Original Data and a Review of the Literature.

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay.

Objective: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy.

Methods: Anthropometric and laboratory data from 7 patients with FHS were described.

Evaluation of SHOX defects in the era of next-generation sequencing.

Short stature homeobox (SHOX) haploinsufficiency is a frequent cause of short stature. Despite advances in sequencing technologies, the identification of SHOX mutations continues to be performed using standard methods, including multiplex ligation-dependent probe amplification (MLPA) followed by Sanger sequencing. We designed a targeted panel of genes associated with growth impairment, including SHOX genomic and enhancer regions, to improve the resolution of next-generation sequencing for SHOX analysis.

Genetic causes of isolated short stature.

Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children.

IGF-1 assessed by pubertal status has the best positive predictive power for GH deficiency diagnosis in peripubertal children.

Background When evaluating peripubertal short stature patients, the interpretation of insulin-like growth factor 1 (IGF-1) levels based on chronological age (CA) can be inaccurate due to the influence of sex steroids and, presently, there is no evidence to support the assessment of IGF-1 values according to bone age (BA) and pubertal status (PS). Our objective was to assess the discriminatory performance of IGF-1 levels based on CA, BA and PS in the diagnosis of growth hormone (GH) deficiency. Methods We evaluated IGF-1 levels from 154 peripubertal short stature patients classified as GH deficient (GHD, n=23) or non-GHD (n=131).

Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature.

Context: Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants.

Objective: To perform a genetic investigation of children with isolated short stature born SGA.

IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy.

Context: Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders.

Objective: To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy.

Patients And Methods: We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders.

Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2.

Background: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response.

Case Presentation: The proband was a healthy boy who presented at the age of 5.

Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia.

Background: Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1).

Methods: Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx.

Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis.

Context: SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature.

Role of the natriuretic peptide system in normal growth and growth disorders.

The C-type natriuretic peptide (CNP) and its receptor (NPR-B) are recognized as important regulators of longitudinal growth. Animal models involving CNP or NPR-B genes (Nppc or Npr2) support the fundamental role of CNP/NPR-B for endochondral ossification. Studies with these animals allow the development of potential drug therapies for dwarfism.

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

Context: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for 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 children with idiopathic short stature (ISS).

Objective: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS.

Patients And Methods: The NPR2 coding region was directly sequenced in 47 independent patients with ISS.

Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly.

Context: GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities.

Objective: The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families.