Inheritance of CHI
The human body is made up of billions of building blocks called cells. Genetic material is located in the form of nuclear-DNA in the cell nucleus. This genetic material carries hereditary information from one generation to the next and contains instructions for cells to make proteins for growth and development. The genetic material is actually condensed in the form of structures called as chromosomes that are like threads of DNA. Each cell contains 46 chromosomes (23 pairs consisting of 22 autosomes and 1 sex chromosome) and each chromosome carries thousands of genes arranged one after another on the chromosomes. An individual gets one chromosome from each of his/her parent and passes them to the next generation. Any alteration in the basic structure of the genes or its arrangement / sequence can lead to a mutation of the gene which can present itself in either autosomal recessive or autosomal dominant pattern.
The human body is made up of billions of building blocks called cells. Genetic material is located in the form of nuclear-DNA in the cell nucleus. This genetic material carries hereditary information from one generation to the next and contains instructions for cells to make proteins for growth and development. The genetic material is actually condensed in the form of structures called as chromosomes that are like threads of DNA. Each cell contains 46 chromosomes (23 pairs consisting of 22 autosomes and 1 sex chromosome) and each chromosome carries thousands of genes arranged one after another on the chromosomes. An individual gets one chromosome from each of his/her parent and passes them to the next generation. Any alteration in the basic structure of the genes or its arrangement / sequence can lead to a mutation of the gene which can present itself in either autosomal recessive or autosomal dominant pattern.
An autosomal recessive pattern means both copies of genes passed on from each parent in the cell has mutations. Whereas in autosomal dominant pattern one copy of the altered gene in passed on from either of the parent.
An autosomal recessive pattern means both copies of genes passed on from each parent in the cell has mutations. Whereas in autosomal dominant pattern one copy of the altered gene in passed on from either of the parent.
Congenital Hyperinsulinism is a genetic disorder with different inheritance patters, usually depending on the form of the condition.
Congenital Hyperinsulinism is a genetic disorder with different inheritance patters, usually depending on the form of the condition.
Diffuse form
Diffuse form
Diffuse form of CHI means a disease involving all the β-cells throughout the islet of pancreas, although with a variable involvement. These account for about 60% of all CHI cases and severe forms are unresponsive to standard medical therapy, requiring a near-total pancreatectomy. However, over the last several years, newer medications have been used to manage this complex severe form of CHI to avoid near-total pancreatectomy.
Diffuse form of CHI means a disease involving all the β-cells throughout the islet of pancreas, although with a variable involvement. These account for about 60% of all CHI cases and severe forms are unresponsive to standard medical therapy, requiring a near-total pancreatectomy. However, over the last several years, newer medications have been used to manage this complex severe form of CHI to avoid near-total pancreatectomy.
The diffuse form of CHI is most often inherited in autosomal recessive pattern, meaning both copies of the gene in each cell has mutations. Both parents of an individual with autosomal recessive condition carry a copy of the mutated gene, but they do not show any signs or symptoms of the conditions and are termed as carriers. However, diffuse form can also be inherited as an autosomal dominant pattern, albeit less frequently, meaning one copy of the altered gene from either of the parent in each cell is mutated.
The diffuse form of CHI is most often inherited in autosomal recessive pattern, meaning both copies of the gene in each cell has mutations. Both parents of an individual with autosomal recessive condition carry a copy of the mutated gene, but they do not show any signs or symptoms of the conditions and are termed as carriers. However, diffuse form can also be inherited as an autosomal dominant pattern, albeit less frequently, meaning one copy of the altered gene from either of the parent in each cell is mutated.
Focal form
Focal form
The focal form of congenital hyperinsulinism (CHI) is characterized by abnormal pancreatic β-cells localized in a specific region of the pancreas. These lesions are generally about 2-10 mm in size and appear as small region of islet cell like clusters with abnormal nuclei of irregular shape. Patients with focal CHI are usually unresponsive to medical therapy and require a surgical lesionectomy for complete cure.
The focal form of congenital hyperinsulinism (CHI) is characterized by abnormal pancreatic β-cells localized in a specific region of the pancreas. These lesions are generally about 2-10 mm in size and appear as small region of islet cell like clusters with abnormal nuclei of irregular shape. Patients with focal CHI are usually unresponsive to medical therapy and require a surgical lesionectomy for complete cure.
The inheritance of focal form of CHI is more complex and in for most genes, both copies, one from either of the parent, are active in all cells. But for a small number of genes, one of the two copies is inactive. In most cases, for the focal form individuals inherit one copy of the mutated, inactive gene from the unaffected father. And during development inside the womb of the mother, a second mutation occurs in the active copy of the gene within the pancreas. This second mutation occurs only in some cells in the pancreas and as a result, only some pancreatic β-cells show abnormal insulin secretion, while the other β-cells function normally.
The inheritance of focal form of CHI is more complex and in for most genes, both copies, one from either of the parent, are active in all cells. But for a small number of genes, one of the two copies is inactive. In most cases, for the focal form individuals inherit one copy of the mutated, inactive gene from the unaffected father. And during development inside the womb of the mother, a second mutation occurs in the active copy of the gene within the pancreas. This second mutation occurs only in some cells in the pancreas and as a result, only some pancreatic β-cells show abnormal insulin secretion, while the other β-cells function normally.
Atypical forms
Atypical forms
In some cases, the pancreatic histology does not fit the typical focal or diffuse appearance and are described as Atypical forms of CHI.
In some cases, the pancreatic histology does not fit the typical focal or diffuse appearance and are described as Atypical forms of CHI.
The need to differentiate between focal and diffuse lesion lies in the fact that the surgical approach differs markedly between the two lesions. Accurate localization and limited removal of the focal lesion can result in complete cure whereas medically unresponsive diffuse disease still require a near-total pancreatectomy, greatly increasing the risk of post-pancreatectomy diabetes mellitus. Moreover, the results from these non-invasive and high accuracy imaging techniques are much better than the traditional imaging methods such as CT and MRI which are not very useful to localize these lesions. But its limitation lies in the limited availability at only a few centers and the expertise required in the interpretation of the images.
The need to differentiate between focal and diffuse lesion lies in the fact that the surgical approach differs markedly between the two lesions. Accurate localization and limited removal of the focal lesion can result in complete cure whereas medically unresponsive diffuse disease still require a near-total pancreatectomy, greatly increasing the risk of post-pancreatectomy diabetes mellitus. Moreover, the results from these non-invasive and high accuracy imaging techniques are much better than the traditional imaging methods such as CT and MRI which are not very useful to localize these lesions. But its limitation lies in the limited availability at only a few centers and the expertise required in the interpretation of the images.
Urgent genetic testing is extremely important in children who are either partial responsive or unresponsive to diazoxide as this will help to differentiate between focal and diffuse forms. Clinicians should arrange to send DNA samples on the child as well as mum and dad. Please discuss with us to arrange for DNA samples to be sent off and for prompt genetic results.
Urgent genetic testing is extremely important in children who are either partial responsive or unresponsive to diazoxide as this will help to differentiate between focal and diffuse forms. Clinicians should arrange to send DNA samples on the child as well as mum and dad. Please discuss with us to arrange for DNA samples to be sent off and for prompt genetic results.