-
European Thyroid Journal Jul 2023Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 years of life, and the negative effects of TH deficiency on brain... (Review)
Review
Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4-TSH-thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.
Topics: Infant, Newborn; Humans; Congenital Hypothyroidism; Neonatal Screening; Thyrotropin; Thyroxine; Thyroid Hormones
PubMed: 37326450
DOI: 10.1530/ETJ-23-0041 -
Best Practice & Research. Clinical... Dec 2023Growth hormone deficiency (GHD) is a common complication of several pituitary and hypothalamic disorders and dependent on the onset of disease. It may have severe... (Review)
Review
Growth hormone deficiency (GHD) is a common complication of several pituitary and hypothalamic disorders and dependent on the onset of disease. It may have severe clinical implications ranging from growth retardation in childhood-onset, to impaired lipid metabolism and increased cardiovascular risk and mortality in adults. GH effectively modulates lipid metabolism at multiple levels and GHD has been associated with an atherogenic lipid profile, that can be reversed by GH replacement therapy. Despite increasing knowledge on the effects of GH on several key enzymes regulating lipid metabolism and recent breakthroughs in the development and wider availability of recombinant GH preparations, several questions remain regarding the replacement therapy in adults with GHD. This review aims to comprehensively summarize the current knowledge on (i) lipid profile abnormalities in individuals with GHD, (ii) proposed mechanisms of action of GH on lipid and lipoprotein metabolism, and (iii) clinical implications of GH replacement therapy in individuals diagnosed with GHD.
Topics: Adult; Humans; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary; Dyslipidemias; Lipids; Growth Hormone; Insulin-Like Growth Factor I
PubMed: 37821339
DOI: 10.1016/j.beem.2023.101821 -
Bone Oct 2023Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter...
Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification.
Topics: Animals; Anion Transport Proteins; Sulfate Transporters; Achondroplasia; Glycosaminoglycans; Biomarkers; Collagen; Sulfates
PubMed: 37454964
DOI: 10.1016/j.bone.2023.116838 -
Dermatologie (Heidelberg, Germany) Sep 2023Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also... (Review)
Review
Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also manifest during natural aging, including vision and hearing loss, atrophy, hair loss, progressive neurodegeneration, and cardiovascular defects. Recent advances in molecular pathology have led to a better understanding of the underlying mechanisms of these diseases. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. While some of those genes encode proteins with a direct involvement in a DNA repair machinery, such as nucleotide excision repair (NER), others destabilize the genome by compromising the stability of the nuclear envelope, when lamin A is dysfunctional in Hutchinson-Gilford progeria syndrome (HGPS) or regulate the DNA damage response (DDR) such as the ataxia telangiectasia-mutated (ATM) gene. Understanding the molecular pathology of progeroid diseases is crucial in developing potential treatments to manage and prevent the onset of symptoms. This knowledge provides insight into the underlying mechanisms of premature aging and could lead to improved quality of life for individuals affected by progeroid diseases.
Topics: Humans; Skin Aging; Quality of Life; Aging; Cockayne Syndrome; Aging, Premature
PubMed: 37650893
DOI: 10.1007/s00105-023-05212-8 -
Deutsches Arzteblatt International Feb 20243% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. (Review)
Review
BACKGROUND
3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders.
METHODS
This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience.
RESULTS
Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management.
CONCLUSION
There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.
Topics: Child; Adult; Humans; Adolescent; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Physicians
PubMed: 38051162
DOI: 10.3238/arztebl.m2023.0247 -
The Journal of Pediatrics Nov 2023
Topics: Humans; Dwarfism; Growth Disorders; Body Height
PubMed: 37543284
DOI: 10.1016/j.jpeds.2023.113659 -
Best Practice & Research. Clinical... Dec 2023Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies... (Review)
Review
Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies have demonstrated evidence that GH treatment improves body composition, cardiovascular risk factors and quality of life with few side effects. Less frequent GH injections are hypothesized to improve adherence and several long-acting GH (LAGH) formulations have been developed and a few have been approved and marketed. Different pharmacological modifications have been applied and the pharmacokinetics and pharmacodynamics of LAGH are different to each other and to those of daily injections and require different dosing and monitoring specific for each LAGH. Studies have shown improved adherence with LAGH, and short-term efficacy and side effects are comparable between daily GH injections and LAGHs. Long-term treatment with daily GH injections is effective and safe, while long-term studies for LAGHs are awaited. In this review challenges, benefits, and risks of treatment with daily and long-acting GH preparations will be compared.
Topics: Adult; Humans; Growth Hormone; Quality of Life; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary
PubMed: 37308376
DOI: 10.1016/j.beem.2023.101788 -
Frontiers in Immunology 2023Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased... (Review)
Review
INTRODUCTION
Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.
METHODS
We present a case of MUL with progressive lymphopenia and review similar cases from the literature.
RESULTS
Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in . Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.
DISCUSSION
The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.
Topics: Female; Humans; Agammaglobulinemia; Heart Failure; Immunoglobulins, Intravenous; Kidney Neoplasms; Lymphopenia; Mulibrey Nanism; Mutation; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wilms Tumor
PubMed: 38116000
DOI: 10.3389/fimmu.2023.1303251 -
Best Practice & Research. Clinical... Dec 2023The predominant features of the adult growth hormone deficiency (GHD) syndrome may vary between patients of different age and age of onset of GHD. Evidence from clinical... (Review)
Review
The predominant features of the adult growth hormone deficiency (GHD) syndrome may vary between patients of different age and age of onset of GHD. Evidence from clinical trials and long-term observational studies has informed our ability to understand the unique considerations regarding risks and benefits of daily growth hormone replacement therapy (GHRT) and specific dosing and monitoring strategies for these patient subgroups. High rates of nonadherence with daily GHRT presents a challenge to achieving optimal treatment outcomes and long-acting growth hormone (LAGH) formulations have been developed with the promise of improving treatment adherence resulting in improved therapeutic outcomes. While existing data from short-term studies have demonstrated noninferiority of efficacy and safety of LAGH compared to daily GHRT, long-term studies are needed to assess the full spectrum of outcomes of interest and long-term safety considerations specific to patients in adolescence, adulthood and the elderly GHD population. Since each LAGH formulation has a unique pharmacodynamic and pharmacokinetic profile optimal dosing and monitoring strategies will need to be developed to allow for the provision of individualized patient treatment.
Topics: Adult; Humans; Adolescent; Aged; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone; Hormone Replacement Therapy; Treatment Outcome
PubMed: 37802712
DOI: 10.1016/j.beem.2023.101825 -
The Science of the Total Environment Nov 2023Overgrazing generally induces dwarfism in grassland plants, and these phenotypic traits could be transmitted to clonal offspring even when overgrazing is excluded....
Overgrazing generally induces dwarfism in grassland plants, and these phenotypic traits could be transmitted to clonal offspring even when overgrazing is excluded. However, the dwarfism-transmitted mechanism remains largely unknown, despite generally thought to be enabled by epigenetic modification. To clarify the potential role of DNA methylation on clonal transgenerational effects, we conducted a greenhouse experiment with Leymus chinensis clonal offspring from different cattle/sheep overgrazing histories via the demethylating agent 5-azacytidine. The results showed that clonal offspring from overgrazed (by cattle or sheep) parents were dwarfed and the auxin content of leaves significantly decreased compared to offspring from no-grazed parents'. The 5-azaC application generally increased the auxin content and promoted the growth of overgrazed offspring while inhibited no-grazed offspring growth. Meanwhile, there were similar trends in the expression level of genes related to auxin-responsive target genes (ARF7, ARF19), and signal transduction gene (AZF2). These results suggest that DNA methylation leads to overgrazing-induced plant transgenerational dwarfism via inhibiting auxin signal pathway.
Topics: Cattle; Animals; Sheep; DNA Methylation; Epigenesis, Genetic; Indoleacetic Acids; Poaceae
PubMed: 37414175
DOI: 10.1016/j.scitotenv.2023.165338