Growth hormone treatment adjusted for growth hormone sensitivity in idiopathic short stature.

Objective: This study aimed to investigate the long-term growth responses to recombinant human growth hormone (rhGH) in children with idiopathic short stature (ISS), decreased insulin-like growth factor I (IGF-1) levels, and a normal stimulated GH peak, after assessing their growth hormone (GH) sensitivity using the IGF-1 generation test (IGFGT).

Design: This was a retrospective descriptive case series.

Methods: One hundred and twenty-nine children with height < -2.

Loss-of-Function GHSR Variants Are Associated With Short Stature and Low IGF-I.

Context: The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knockout mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal.

Genetic Findings in Short Turkish Children Born to Consanguineous Parents.

Introduction: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented.

Methods: This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used.

Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing.

Assessment of Nutritional Status in the Diagnostic Evaluation of the Child with Growth Failure.

Current clinical guidelines provide information about the diagnostic workup of children with growth failure. This mini-review focuses on the nutritional assessment, which has received relatively little attention in such guidelines. The past medical history, in particular a low birth size and early feeding problems, can provide information that can increase the likelihood of nutritional deficits or several genetic causes.

Long-acting PEGylated growth hormone in children with idiopathic short stature: time to reconsider our diagnostic and treatment policy?

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated. Idiopathic short stature is an approved indication for recombinant human growth hormone (rhGH) in the USA but not in most other parts of the world.

A Novel Pathogenic IGSF1 Variant in a Patient with GH and TSH Deficiency Diagnosed by High Values at Transition to Adult Care.

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations.

Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying Mutations.

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism.

Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion.

The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak ("GH neurosecretory dysfunction," GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI).

IGSF1 Does Not Regulate Spermatogenesis or Modify FSH Synthesis in Response to Inhibins or Activins.

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 () gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis.

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth.

Our objective was to further expand the spectrum of clinical characteristics of the deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood.

[A child with inexplicable alteration of consciousness].

A 4-year-old girl presented with an alteration of consciousness and absence of speech after a short period of vomiting, diarrhoea and fever. MRI of the brain revealed a focal lesion in the splenium of the corpus callosum. Rotavirus was detected in the faeces.

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects.

Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common.

IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.

Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects.

From Consternation to Revelation: Discovery of a Role for IGSF1 in Pituitary Control of Thyroid Function.

Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein highly expressed in the mammalian pituitary gland. Shortly after its discovery in 1998, the protein was proposed to function as a coreceptor for inhibins (and was even temporarily renamed inhibin binding protein). However, subsequent investigations, both and , failed to support a role for IGSF1 in inhibin action.

The short mRNA isoform of the immunoglobulin superfamily, member 1 gene encodes an intracellular glycoprotein.

Mutations in the immunoglobulin superfamily, member 1 gene (IGSF1/Igsf1) cause an X-linked form of central hypothyroidism. The canonical form of IGSF1 is a transmembrane glycoprotein with 12 immunoglobulin (Ig) loops. The protein is co-translationally cleaved into two sub-domains.

TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice.

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotropin (TSH)-producing thyrotrope cells of the anterior pituitary gland. The protein is cotranslationally cleaved, with only its C-terminal domain (CTD) being trafficked to the plasma membrane.

Mutations in TBL1X Are Associated With Central Hypothyroidism.

Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex.

Quality of life in patients with adrenal insufficiency correlates stronger with hydrocortisone dosage, than with long-term systemic cortisol levels.

In patients with adrenal insufficiency (AI) a higher hydrocortisone intake has been associated with more impairment in quality of life (QoL). Irrespective of age, sex and severity of AI the dosage of hydrocortisone is titrated around 20mg/D in all patients with AI based on physical and mental signs and symptoms. However, until now it is unknown whether these QoL impairments are related to increased systemic cortisol exposure.

Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome.

Background: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency.

Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat.

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is imperative. Therefore, we investigated spatial and temporal protein and mRNA expression of IGSF1 in rats using immunohistochemistry, real-time quantitative PCR (qPCR), and in situ hybridization.

New reference charts for testicular volume in Dutch children and adolescents allow the calculation of standard deviation scores.

Aim: Accurate calculations of testicular volume standard deviation (SD) scores are not currently available. We constructed LMS-smoothed age-reference charts for testicular volume in healthy boys.

Methods: The LMS method was used to calculate reference data, based on testicular volumes from ultrasonography and Prader orchidometer of 769 healthy Dutch boys aged 6 months to 19 years.