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Contributions to the Study of the Etiology of a Cardiovascular Disorder:

Congenital Heart Disease (CHD) at Birth and into Adulthood: The Role of Spontaneous Mutations

Curator: Aviva Lev-Ari, PhD, RN

 

THE ETIOLOGY OF Congenital Heart Disease (CHD)

Congenital heart disease is a problem with the heart’s structure and function that is present at birth.

Causes

Congenital heart disease (CHD) can describe a number of different problems affecting the heart. It is the most common type of birth defect. Congenital heart disease causes more deaths in the first year of life than any other birth defects.

Congenital heart disease is often divided into two types: cyanotic (blue skin color caused by a lack of oxygen) and non-cyanotic. The following lists cover the most common congenital heart diseases:

Cyanotic:

Non-cyanotic:

These problems may occur alone or together. Most children with congenital heart disease do not have other types of birth defects. However, heart defects can be part of genetic and chromosome syndromes. Some of these syndromes may be passed down through families.

Examples include:

Often, no cause for the heart disease can be found. Congenital heart diseases continue to be investigated and researched. Drugs such as retinoic acid for acne, chemicals, alcohol, and infections (such as rubella) during pregnancy can contribute to some congenital heart problems.

Poorly controlled blood sugar in women who have diabetes during pregnancy has also been linked to a high rate of congenital heart defects.

Symptoms

Symptoms depend on the condition. Although congenital heart disease is present at birth, the symptoms may not appear right away.

Defects such as coarctation of the aorta may not cause problems for many years. Other problems, such as a small ventricular septal defect (VSD), may never cause any problems. Some people with a VSD have a normal activity level and lifespan.

Exams and Tests

Most congenital heart defects are found during a pregnancy ultrasound. When a defect is found, a pediatric heart doctor, surgeon, and other specialists can be there when the baby is delivered. Having medical care ready at the delivery can mean the difference between life and death for some babies.

Which tests are done on the baby depend on the defect, and the symptoms.

Treatment

Which treatment is used, and how well the baby responds to it, depends on the condition. Many defects need to be followed carefully. Some will heal over time, while others will need to be treated.

Some congenital heart diseases can be treated with medication alone. Others need to be treated with one or more heart surgeries.

Prevention

Women who are expecting should get good prenatal care:

  • Avoid alcohol and illegal drugs during pregnancy.
  • Tell your doctor that you are pregnant before taking any new medicines.
  • Have a blood test early in your pregnancy to see if you are immune to rubella. If you are not immune, avoid any possible exposure to rubella and get vaccinated right after delivery.
  • Pregnant women who have diabetes should try to get good control over their blood sugar levels.

Certain genes may play a role in congenital heart disease. Many family members may be affected. Talk to your health care provider about genetic screening if you have a family history of congenital heart disease.

The Role of Spontaneous Mutations – The Genes and The Pathways:

Contributing Researchers’ Bio

Richard P. Lifton, M.D., Ph.D.
HHMI INVESTIGATOR
1994– Present
Yale School of Medicine
Education
bullet icon B.A., biological sciences, Dartmouth College
bullet icon M.D., Stanford University School of Medicine
bullet icon Ph.D., biochemistry, Stanford University
Member
bullet icon National Academy of Sciences
bullet icon Institute of Medicine
bullet icon Association of American Physicians
bullet icon Lasker Award Jury
bullet icon American Academy of Arts and Sciences
Awards
bullet icon Homer Smith Award, American Society of Nephrology
bullet icon Richard Bright Award, American Society of Hypertension
bullet icon The Basic Research Prize, American Heart Association
bullet icon Robert Tigerstedt Award, International Society of Hypertension
bullet icon A.N. Richards Award, International Society of Nephrology
bullet icon Wiley Prize in Biomedical Sciences
Richard P. Lifton, M.D., Ph.D.
Richard P. Lifton

Twenty years ago, when Richard Lifton first proposed using genetic methods to study the causes of high blood pressure, his approach was not uniformly accepted. Such a complicated condition, critics thought, would not lend itself to traditional genetic tactics, which try to link a disease to alterations in a single gene.

Since then, Lifton has proved his detractors wrong many times over. Lifton has identified more than 20 genes associated with blood pressure, cardiovascular disease, and bone density, and he has characterized mutations that cause either extreme hypertension (high blood pressure) or hypotension (low blood pressure) in people.

More significantly, he has shown that severe blood pressure problems can be caused by mutations in genes that regulate the amount of sodium chloride the kidney allows to flow into the blood. When these genes falter in severe hypertension cases, salt levels rise, blood volume increases, the heart pumps harder, and blood pressure surges. With excessive hypotension, the opposite occurs. Today, his findings have changed how doctors treat hypertension, which affects approximately 1 billion people worldwide and is the most prevalent cardiovascular disease risk factor.

At the time Lifton started looking for blood pressure genes, scientists and clinicians did not know if the brain, cardiovascular system, adrenal gland, or kidney was the primary source of the problem. Cardiologists tended to consider the heart or the vascular system as the blood pressure regulator. Others thought the adrenal gland hormone aldosterone, which regulates blood salt and potassium levels, was the master controller.

To better understand hypertension’s pathophysiology, Lifton borrowed the concept behind classic fruit fly genetics and applied it to humans. Scientists would treat insects with mutagens and see dramatic effects in progeny wing shape or eye color and then find the gene that caused the altered trait. Since mutagenesis experiments cannot be performed in humans, Lifton instead sought the most extreme cases of severe blood pressure disease. A person with hypertension needing treatment has blood pressure readings above 140/90. But Lifton was interested in rare individuals with both very high and low measurements.

Physicians and scientists throughout the world have contacted him. “Today, people even find me on the Internet,” he says. Lifton studies the families, determines inheritance patterns, takes blood samples, and ultimately localizes genes and mutations responsible for their conditions. He estimates he has collected blood samples from more than 10,000 people.

“I always have been struck by how willing people are to participate in research when a disease runs in their families,” Lifton said. “They know how the disease impacts their family and hope research might lead to benefits to future generations in their family and in others, too.”

In 1994, Lifton first showed that a mutation in the kidney (in a sodium channel) could cause severe hypertension. “It was the first paper to demonstrate a mutation intrinsic to the kidney was critical for blood pressure homeostasis,” Lifton said. Since then, he has found mutations in 10 kidney genes that raise blood pressure and mutations in 9 kidney genes that lower blood pressure. All the mutations affect how the kidney regulates salt levels in the blood.

Collectively, his work provided the scientific underpinnings for new national hypertension treatment guidelines. They recommend that most patients with hypertension take drugs called diuretics, which lower blood pressure by reducing kidney salt reabsorption. Reabsorption is when the kidney returns salt, glucose, and other plasma components back into the bloodstream after it has removed substances it will excrete in the urine.

“Before these recommendations, hypertension treatment used to be completely empiric,” Lifton said, with doctors choosing among 70 different drugs that acted on the heart, blood vessels, or elsewhere, and seeing what worked for individual patients. His research also revealed the reason for a major side effect of diuretics, which is that patients crave and inadvertently consume excess salt, defeating the drug’s purpose. Such patients now are given another drug that represses their desire to eat salt.

Although hypertension treatment has improved in the past two decades, less than a third of patients have their blood pressure adequately controlled because drugs do not work. As a result, they are more likely to have a heart attack or stroke. To bring better antihypertensive drugs to market, Lifton uses his knowledge about the kidney gene pathway and other novel cardiovascular disease genes he has discovered and collaborates with pharmaceutical industry scientists.

Meanwhile, utilizing the new tools of genomics, which analyze many genes simultaneously, Lifton is searching for variations in the genes he first identified in rare cases to determine their possible contributions to blood pressure problems in the general population. Such research could lead to individualized treatment based on a genetic profile. With these new technologies, it may also be possible to prevent hypertension before damage occurs.

Lifton pursued medicine and research because he was inspired as a boy by President John Kennedy’s call to public service. “Working with patients to understand human disease,” he said “and advancing knowledge and treatment is an enterprise of infinite fascination and reward.”

Dr. Lifton is also Sterling Professor of Genetics and Internal Medicine at Yale School of Medicine.


RESEARCH ABSTRACT SUMMARY:
Richard Lifton uses genetic approaches to identify the genes and pathways that contribute to common human diseases, including cardiovascular, renal, and bone disease.

View Research Abstractsmall arrow

Photo: Gayle Zucker

Christine E. Seidman, M.D. – Bio
HHMI INVESTIGATOR
1994– Present
Brigham and Women’s Hospital
Education
bullet icon B.S., biochemistry, Harvard University
bullet icon M.D., George Washington University
Member
bullet icon American Academy of Arts and Sciences
bullet icon American Heart Association Distinguished Scientists (Council on Basic Cardiovascular Science)
bullet icon Johns Hopkins University Society of Scholars
bullet icon Institute of Medicine, National Academy of Sciences
bullet icon National Academy of Sciences
Awards
bullet icon American Heart Association, Basic Science Prize
bullet icon American Society for Clinical Investigation Award
bullet icon Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular Research
bullet icon Robert J. and Claire Pasarow Foundation Award in Cardiovascular Research
bullet icon Grand Prix Lefoulon-Delalande, Institute of France
bullet icon Schottenstein Prize in Cardiovascular Science, Ohio State University
Christine E. Seidman, M.D.Christine E. Seidman

Though no one in her family was a physician, Christine Seidman always wanted to be a doctor. But the word had a slightly different meaning for her than it does for most. “To me, that was a person who was medically trained and took care of sick people, but who also really understood why they got sick…Some people think you’re a physician or a scientist. To me, they’re synonymous. I still think that.”

Seidman—who goes by Kricket (thanks to a young cousin who couldn’t pronounce “Christine”)—met her husband and research partner, Jon, when they were both undergraduates at Harvard. “We had a lab research project that we had to design and have approved. My group’s project was not approved. So they split up our group and reassigned us to other projects, and I got assigned to Jon’s group.”

The two were married during Seidman’s junior year. After graduation and medical school, Seidman headed to Johns Hopkins for her residency and internship “because it spoke science to me.” She was there for three years before moving to Boston, where she did a cardiology fellowship at Massachusetts General Hospital before finishing her training in Baltimore.

At MGH, Seidman worked with a group led by the late Edgar Haber, trying to isolate and clone the genes for adrenergic receptors, which are important in cardiovascular physiology. She then became interested in atrial natriuretic peptide, or ANP. Released by the heart, ANP regulates salt and water in the bloodstream to reduce blood pressure. A partial amino acid sequence of this natriuretic peptide had just been published, and Seidman was intrigued; studying ANP had broad implications for treatment of high blood pressure. “As a cardiologist, you think this might cure hypertension.”

She moved to her husband’s lab at Harvard Medical School, where she cloned the ANP cDNA and gene. The two have worked together ever since, studying the effects of genetic variation in heart disease.

In 1998, she began studying disorders of heart muscle. Seidman’s work began with familial hypertrophic cardiomyopathy (HCM), which increases heart thickness and predisposes to the development of heart failure and sudden death. HCM is the most common cause of sudden death on the athletic field; it also affects many more people than originally thought. Seidman used genetic approaches to discover mutations that altered proteins involved in heart muscle contraction. This work enabled the development of models that can help researchers understand the mechanisms by which mutations cause disease. The work also allowed for gene-based diagnosis of HCM.

Seidman’s group also has identified gene mutations that cause dilated cardiomyopathy and congenital heart malformations.

To understand how gene mutations affect heart structure and function, Seidman’s laboratory does much of their work in mouse models. “If you know that a gene abnormality causes disease, you ought to be able to stick that gene into a cell and figure out the pathways it affects and what it does. But we don’t have any cell lines in cardiology. So we put the genes into mice and let them get heart disease and then study the heart.”

Most recently, Seidman used mice genetically destined for heart disease and a gene-sequencing technique called PMAGE to identify hundreds of early-acting genes that could be responsible for hypertrophic cardiomyopathy. This type of work could help scientists define the pathways that lead to cellular changes in this disease and other cardiac diseases, as well as identify targets for potential drug therapies.

“PMAGE represents an approach for mechanistic understanding of cardiac disease,” she says. “It’s a really in-depth way to look for genes that change early and cause responses that ultimately equal disease. We ought to be able to learn from these changes and perhaps alter them, so as to prevent or diminish the subsequent development of disease. While today this approach makes use of animal models, it will be equally powerful when applied to study diseased heart tissues from patients.”

The Seidmans have three children—14-year-old Gregor; 21-year-old Seth, a history major at Brown; and 25-year-old Nika, a medical student at Harvard. They live in Milton, Massachusetts, which Seidman likes because of its relatively rural flavor.

Outside the lab, “I am into heavy-duty gardening,” she says. “It’s more like landscape architecture. I think in my next life, I’ll be a botanist.”

Dr. Seidman is also Professor of Genetics and Medicine at Harvard Medical School and Director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.


RESEARCH ABSTRACT SUMMARY:
Christine Seidman is interested in understanding the genetic basis of human cardiovascular disorders such as cardiomyopathy (hypertrophic and dilated), heart failure, and congenital heart malformations. Using experimental models that are engineered to carry human mutations, her lab examines the consequences of mutations on cardiac biology that lead to clinical manifestations of disease. She hopes to combine knowledge of genetic etiologies and molecular mechanisms to improve therapeutic opportunities for patients.

View Research Abstractsmall arrowPhoto: Justin Knight

HOWARD HUGES MEDICAL INSTITUTE ANNOUNCEMENT:


MAY 12, 2013
Spontaneous Mutations Play a Key Role in Congenital Heart Disease

Every year, thousands of babies are born with severely malformed hearts, disorders known collectively as congenital heart disease. Many of these defects can be repaired though surgery, but researchers don’t understand what causes them or how to prevent them. New research shows that about 10 percent of these defects are caused by genetic mutations that are absent in the parents of affected children.

Although genetic factors contribute to congenital heart disease, many children born with heart defects have healthy parents and siblings, suggesting that new mutations that arise spontaneously—known as de novomutations—might contribute to the disease. “Until recently, we simply didn’t have the technology to test for this possibility,” says Howard Hughes Medical Institute (HHMI) investigator~Richard Lifton. Lifton, who is at Yale School of Medicine, together with Christine Seidman, an HHMI investigator at Brigham and Women’s Hospital and colleagues at Columbia, Mt. Sinai, and the University of Pennsylvania, collaborated to study congenital heart disease through the National Heart Lung and Blood Institute’s Pediatric Cardiac Genomics Consortium.


“The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart.”
Christine E. Seidman

Using robust sequencing technologies developed in recent years, the researchers compared the protein-coding regions of the genomes of children with and without congenital heart disease and their parents, and found that new mutations could explain about 10 percent of severe cases. The results demonstrated that mutations in several hundred different genes contribute to this trait in different patients, but were concentrated in a pathway that regulates key developmental genes. These genes affect the epigenome, a system of chemical tags that modifies gene expression. The findings were published online in the journal Nature on May 12, 2013.

For the current study, the investigators began with 362 families consisting of two healthy parents with no family history of heart problems and a child with severe congenital heart disease. By comparing genomes within families, they could pinpoint mutations that were present in each child’s DNA, but not in his or her parents. The team also studied 264 healthy families to compare de novo mutations in the genomes of healthy children.

The team focused their gene-mutation search on the exome – the small fraction of each person’s genome that encodes proteins, where disease-causing mutations are most likely to occur. Children with and without congenital heart disease had about the same number of de novomutations — on average, slightly less than one protein-altering mutation each. However, the locations of those mutations were markedly different in the two groups. “The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart,” Seidman says.

The differences became more dramatic when the researchers zeroed in on mutations most likely to impair protein function, such as those that would cause a protein to be cut short. Children with severe congenital heart disease were 7.5 times more likely than healthy children to have a damaging mutation in genes expressed in the developing heart.

The researchers found mutations in a variety of genes, but one cellular pathway was markedly enriched in the children with heart defects. That pathway helps regulate gene activity by affecting how DNA is packaged inside cells. The body’s DNA is wrapped around proteins called histones, and chemical tags called methyl groups are added to histones to control which genes are turned on and off. In children with congenital heart disease, the team found an excess of mutations in genes that affect histone methylation at two sites that are known to regulate key developmental genes.

Overall, the researchers found that de novo mutations contribute to 10 percent of cases of severe congenital heart disease. Roughly a third of this contribution is from the histone-methylation pathway, Lifton says. He also notes that a mutation in just one copy of a gene in this pathway was enough to markedly increase the risk of a heart defect.

Direct sequencing of protein-coding regions of the human genomes to hunt down de novo mutations has only been applied to one other common congenital disease—autism. In that analysis, Lifton and his colleagues at Yale, as well as HHMI investigator Evan Eichler and colleagues at University of Washington, found mutations in some of the same genes mutated in congenital heart disease, and the same histone modification pathway appears to play a major role in autism as well, raising the possibility that this pathway may be perturbed in a variety of congenital disorders, Lifton says.

Even if the disease can’t be prevented, identifying the mutations responsible for severe heart defects might help physicians better care for children with congenital heart disease. “After we repair the hearts of these children, some children do great and some do poorly,” Seidman says. Researchers have long suspected that this might be due to differences in the underlying causes of the disease. Understanding those variations might help doctors improve outcomes for their patients.

HARVARD MEDICAL SCHOOL NEWS:
Spontaneous Mutations – Findings clarify genetic puzzle in heart condition that affects thousands of newborns each year
May 15, 2013

3D computer generated image of chromosomes. Image: cdascher/iStock3D computer generated image of chromosomes. Image: cdascher/iStock

Every year, thousands of babies are born with severely malformed hearts, disorders known collectively as congenital heart disease. Many of these defects can be repaired though surgery, but researchers don’t understand what causes them or how to prevent them.

Although genetic factors contribute to congenital heart disease, new research shows that about 10 percent of these defects are caused by genetic mutations that are absent in the parents and siblings of affected children, suggesting that new mutations that arise spontaneously—known as de novo mutations—might contribute to the disease.

“Until recently, we simply didn’t have the technology to test for this possibility,” said Richard Lifton, chair of the department of genetics at Yale School of Medicine.

Lifton, who is also a Howard Hughes Medical Institute (HHMI) investigator, together with Christine Seidman, a Harvard Medical School professor of genetics at Brigham and Women’s Hospital, as well as colleagues at Columbia, Mt. Sinai and the University of Pennsylvania, collaborated to study congenital heart disease through the National Heart Lung and Blood Institute’s Pediatric Cardiac Genomics Consortium.

Overall, the researchers found that of the de novo mutations that contribute to 10 percent of severe congenital heart disease cases, roughly a third are from the histone-methylation pathway. Lifton noted that a mutation in just one copy of a gene in this pathway was enough to markedly increase the risk of a heart defect.

Direct sequencing of protein-coding regions of the human genomes to hunt down de novo mutations has only been applied to one other common congenital disease — autism. In that analysis, Lifton and his colleagues at Yale, as well as HHMI investigator Evan Eichler and colleagues at University of Washington, found mutations in some of the same genes mutated in congenital heart disease. The same histone modification pathway appears to play a major role in autism as well, raising the possibility that this pathway may be perturbed in a variety of congenital disorders, Lifton said.

Even if the disease can’t be prevented, identifying the mutations responsible for severe heart defects might help physicians better care for children with congenital heart disease.

“After we repair the hearts of these children, some children do great and some do poorly,” Seidman said.

Researchers have long suspected that this might be due to differences in the underlying causes of the disease. Understanding those variations might help doctors improve outcomes for their patients.

Histone-methylation pathway research

Using robust sequencing technologies developed in recent years, the researchers compared the protein-coding regions of the genomes of children with and without congenital heart disease and their parents, and found that new mutations could explain about 10 percent of severe cases.

The results demonstrated that mutations in several hundred different genes contribute to this trait in different patients, but were concentrated in a pathway that regulates key developmental genes. These genes affect the epigenome, a system of chemical tags that modifies gene expression. The findings were published online in the journal Nature on May 12, 2013.

For the current study, the investigators began with 362 families consisting of two healthy parents with no family history of heart problems and a child with severe congenital heart disease. By comparing genomes within families, they could pinpoint mutations that were present in each child’s DNA, but not in his or her parents.

The team also studied 264 healthy families to compare de novo mutations in the genomes of healthy children.

Christine SeidmanChristine SeidmanThe team focused their gene-mutation search on the exome — the small fraction of each person’s genome that encodes proteins, where disease-causing mutations are most likely to occur. Children with and without congenital heart disease had about the same number of de novomutations — on average, slightly less than one protein-altering mutation each. However, the locations of those mutations were markedly different in the two groups.

“The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart,” said Seidman, who is also an HHMI investigator.

The differences became more dramatic when the researchers zeroed in on mutations most likely to impair protein function, such as those that would cause a protein to be cut short. Children with severe congenital heart disease were 7.5 times more likely than healthy children to have a damaging mutation in genes expressed in the developing heart.

The researchers found mutations in a variety of genes, but one cellular pathway was markedly enriched in the children with heart defects. That pathway helps regulate gene activity by affecting how DNA is packaged inside cells. The body’s DNA is wrapped around proteins called histones, and chemical tags called methyl groups are added to histones to control which genes are turned on and off.

In children with congenital heart disease, the team found an excess of mutations in genes that affect histone methylation at two sites that are known to regulate key developmental genes.

Adapted from HHMI news release.

 http://hms.harvard.edu/news/spontaneous-mutations-5-15-13

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Intersexuality: Management of Patients

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Introduction

Humans can be immensely strong and adaptable. Certainly some intersexed individuals can, in dignity, maintain themselves in a manner that they neither would have chosen nor in which they feel comfortable — as have others with a life condition from birth that cannot be changed (from cleft palate to meningomyelocele).

Many can adjust to surgery and reassignment for which they were not consulted and many have learned to accept secrecy, misrepresentations, white and black lies and loneliness. People make life accommodations every day and try to better their lot for tomorrow. Many individuals that have come to terms with their life regardless of how stressed or painful.

However, there are individuals who have been given neonatal surgery for cleft palate or meningomyelocele, many of those who have had genital surgery or been sex reassigned neonatally have complained bitterly of the treatment. Some have sex reassigned themselves. Others treated similarly have reasons not to make an issue of the matter but are living in silent despair but coping.

Guidelines

  • In all cases of ambiguous genitalia, to establish most probable cause, do a complete history and physical. The physical must include careful evaluation of the gonads and the internal as well as external genital structures. Genetic and endocrine evaluations are usually needed and interpretation can require the assistance of a pediatric endocrinologist, radiologist and urologist. Pelvic ultrasonography and genitography may be required. Do not hesitate to seek expert help; a team effort is best. The history must include assessment of the immediate and extended family.Be rapid in this decision making but take as much time as needed. Hospitals should have established House Staff Operating Procedures to be followed in such cases. Many consider this a medical emergency (and in cases of electrolyte imbalance this may be immediately so) nevertheless, it is believed that most doubt should be resolved before a final determination is made. It is simultaneously advised that all births be accompanied by a full genital inspection. Many cases of intersex go undetected.
  • Immediately, and simultaneously with the above, advise parents of the reasons for the delay. Full and honest disclosure is best and counseling must start directly. Insure that the parents understand this condition is a natural variety of intersex that is uncommon or rare but not unheard of. Convey strongly to the parents that they are not at fault for the development and the child can have a full, productive and happy life. Repeat this counseling at the next opportunity and as often as needed.
  • The child’s condition is nothing to be ashamed of but it is also nothing to be broadcast as a hospital curiosity. The child and family confidentiality must be respected.
  • In the most common cases, those of hypospadias and congenital adrenal hyperplasia (C.A.H.) diagnosis should be rapid and clear. In other situations, with a known diagnosis, declare sex based on the most likely outcome for the child involved. Encourage the parents to accept this as best; their desire as to sex of assignment is secondary. The child remains the patient. When assignment is based on the most likely outcome, most children will adapt and accept their gender assignment and it will coincide with their sexual identity.
  • The sex of assignment, when based on the nature of the diagnosis rather than only considering the size or functionality of the phallus, respects the idea that the nervous system involved in adult sexuality has been influenced by genetic and endocrine events that will most likely become manifest with or after puberty. In the majority of cases this sex of assignment will indeed be in concert with the appearance of the genitalia. In certain childhood situations, however, such assignment will be counter to the genital appearance (e.g., for reductase deficiency). The concern is primarily how the individual will develop and prefer to live post puberty when he or she becomes most sexually active.

Rear as male:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 1-3)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with extensively fused labia and a penile clitoris

XY individuals with Hypospadias

Persons with Klinefelter syndrome

XY individuals with Micropenis

XY individuals with 5-alpha or 17-beta reductase deficiency

Rear as female:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 4-7)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with hypertrophied clitoris

XX individuals with Gonadal dysgenesis

XY individuals with Gonadal dysgenesis

Persons with Turner’s syndrome

For those individuals with mixed gonadal dysgenesis (MGD) assign male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. The genital appearance of individuals with MGD can range from that of a typical Turner’s syndrome to that of a typical male. Evaluation of high male-like testosterone levels in these cases is also rationale for male assignment.

True hermaphrodites should be assigned male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. If there is a micropenis, assign as male. Admittedly, in some cases a clear diagnosis is not possible, the genital appearance will seem equally male as female and prediction as to future development and gender preference is difficult. There is little evidence a poorly functioning clitoris and vagina is any better than a poorly functioning penis and there is no higher reason to save the reproductive capacity of ovaries over testes. In such difficult cases, whichever decision is made, the likelihood of the individual independently switching gender remains. The medical team in such cases will be taxed to make the best management decision.

  • While sex determination is ongoing, the hospital administration can wait for a final diagnosis before entering a sex of record and Staff can refer to the child as “Infant Jones” or “Baby Brown.” After a sex designation has been made, naming and registration can occur. In those cases mentioned above, where prediction of future outcome is in doubt, parents might consider that a name be used that is appropriate for either males or females (e.g., Lee, Terry, Kim, Francis, Lynn, etc.).
  • Perform no major surgery for cosmetic reasons alone; only for conditions related to physical/medical health. This will entail a great deal of explanation needed for the parents who will want their children to “look normal.” Explain to them that appearances during childhood, while not typical of other children, may be of less importance than functionality and post pubertal erotic sensitivity of the genitalia. Surgery can potentially impair sexual/erotic function. Therefore such surgery, which includes all clitoral surgery and any sex reassignment, should typically wait until puberty or after when the patient is able to give truly informed consent.
  • Major prolonged steroid hormone administration (other than for management of C.A.H.) too should require informed consent. Many intersex or sex reassigned individual’s have felt they were not consulted about their use and effects and regretted the results.
  • In individuals with A.I.S, do not remove gonads for fear of potential tumor growth; such tumors have not been reported to occur in prepubertal children. Retention of the gonads will forestall the need for hormone replacement therapy and possibly help reduce osteoporosis.Furthermore, delaying gonadectomy until after puberty will allow the young woman to come to terms with her diagnosis, understand the reason for her surgery and participate in the decision.
  • Advice regarding gonad removal from true hermaphrodites, individuals with streak gonads and others where malignancies can potentially occur is not so clear. Prophylactically it is common to remove these early; particularly in cases of gonadal dysgenesis.Watchful waiting with frequent checks is always prudent. It is suggested, whenever the gonads are removed, is to explain as best as possible why the procedure is needed and attempt to get consent. If the child is too young to understand the reason for the surgery, its necessity should be explained as early as possible.
  • In rearing, parents must be consistent in seeing their child as either a boy or girl; not neuter. In the society intersex is a designation of medical fact but not yet a commonly accepted social designation. With age and experience, however, an increasing number of hermaphroditic and pseudohermaphroditic individuals are adopting this identification. In any case, advise parents to allow their child free expression as to choices in toy selection, game preference, friend association, future aspirations and so forth.
  • Offer advice and tips on how to meet anticipated situations, e.g., how to deal with grandparents, siblings, baby sitters and others that might question the child’s genital appearance (e.g., “He/she is different but normal. When the child is older he/she and the doctors will do what seems best.”) Parents should minimize the opportunities for such questioning by strangers.
  • Be clear that the child is special and, in some cases might, before or after puberty, accept life as a tomboy or a sissy or even switch gender altogether. The individual may demonstrate androphilic, gynecophilic or ambiphilic orientation. These behaviors are not due to poor parental supervision but will be related to an interaction of the biological, psychological, social and cultural forces to which a child with intersexuality is subject. Some individuals will be quite sexually active and others will be altogether reserved and have little or no interest in sexual relationships.
  • The patient’s special situation will require guidance as to how to meet potential challenges from parents, peers and strangers. He or she will need love and friendly support.Not all parents will be helpful, understanding, or benign and childhood, adolescent, and adult peers can be cruel. Positive peer interaction should be facilitated and encouraged.
  • Maintain contact with family so that counsel is available particularly at crucial times.Counseling should be multi-staged (at birth, and at least again at age two, at school entry, prior to and during pubertal changes, and yearly during adolescence) and it should be detailed and honest. Counseling should be straight-forward, neither patronizing or paternalistic, to parents and to the child as he or she develops with as much full disclosure as the parents and child can absorb. The counseling should ideally be by those trained in sexual/gender/intersex matters.
  • As the child matures there must be opportunity for private counseling sessions and it is essential the door remains open for additional consultation as needed. On the one hand, the full impact of the situation will not always be immediately apparent to the parents or child. On the other hand, they might magnify the developmental potential of the genital ambiguity. As above, the counseling should ideally be by those trained in sexual/gender/intersex matters.
  • Counseling must include developmental sequelae to be anticipated. This should be along medical/biological lines and along social/psychological lines. Do not avoid honest and frank talk of sexual and erotic matters. Discuss the probabilities of puberty such as the presence or absence of menses and the potential for fertility or infertility. Contraception advice may be needed and safe-sex advice is always warranted. Certainly the full gamut of heterosexual, homosexual, bisexual and even celibate options –however these are interpreted by the patient– must be offered and candidly discussed. Adoption possibilities can be broached for those that will be infertile. It is better to discuss these issues early rather than late. Do not obfuscate; knowledge is power enabling the individuals to structure their lives accordingly.
  • The family should be encouraged to openly discuss the situation among themselves, with and without a counselor present, so the child and parents can honestly come to terms with whatever the future holds. Parents have to understand their child’s needs and feelings and the child has to understand the concerns of the parents.
  • As early as possible put the family in touch with a support group. There are such groups for individuals with Androgen Insensitivity Syndrome, Congenital Adrenal Hyperplasia, Klinefelter Syndrome, and Turner’s Syndrome. Intersexed individuals as a whole (hermaphrodites and pseudohermaphrodites of all etiologies) have a support group, the Intersex Society of North America [addresses for these groups are listed below]. It is emphasized that one on one contact with another person having similar experiences can be the most uplifting factor in an intersexed person’s healthy development! Individual groups or chapters might be more inclined toward parental concerns while others might be tilted toward the intersexed person’s concerns. Both perspectives are needed and separate meetings for each faction are useful. Parents need to talk about their feelings in an environment free of intersexed children and adults and the intersexed children and adults similarly need to be able to discuss their feelings and concerns free of their parents. There are times when it is appropriate for physicians to be present and times when it is not.
  • Keep genital inspection to a minimum and request permission for inspection even from a child. Hold in mind that a child may not feel able to deny a physician’s request even though that might be his/her wish. The individuals must come to realize that their genitals are their own and they, not the doctors, parents or anyone else, have control over them. Allow others to view the patient only with his or her permission. Often the genital inspections themselves become traumatic events.
  • Let the child grow and develop as normally as possible with a minimum of interference other than needed for medical care and counseling. Let him/her know that help is available if needed. Listen to the patient; even when as a child. The physician should be seen as a friend.
  • With increasing maturity the designation of intersex may be acceptable to some and not to others. It should be offered as an optional identity along with male and female.
  • As puberty approaches be open and honest with the endocrine and surgical options and life choices available. Be candid at the sexual/erotic and other trade-offs involved with surgery or gender change and insure that any decision finally be that of the fully informed individual regardless of age. To have him/her discuss the treatment with someone who has undergone the procedure is ideal.
  • Most individuals are convinced by the age of 10-15 as to the direction that would be most suitable for them; male or female. Some decisions, however, should be stalled as long as possible to increase the likelihood that the individual has some experience with which to judge. For instance, a female with a phallic clitoris, sexually inexperienced with partner or masturbation, may not realize the loss in genital sensitivity and responsivity that can accompany cosmetic clitoral reduction. Insure that sufficient information is provided to aid in any decision.
  • Most intersex conditions can remain without any surgery at all. A woman with a phallus can enjoy her hypertrophied clitoris and so can her partner. Women with the androgen insensitivity syndrome or virilizing congenital adrenal hyperplasia who have smaller than usual vaginas can be advised to use pressure dilation to fashion one to facilitate coitus; a woman with partial A.I.S. likewise can enjoy a large clitoris. A male with hypospadias might have to sit to urinate without mishap but can function sexually without surgery. An individual with a micropenis can satisfy a partner and father children.There is disagreement as to whether gonads that might prove masculinizing or feminizing at puberty should be removed early on to prevent such changes in a child that does not desire such changes. The disagreement involves the concept that the individual faced with such changes might actually come to prefer them to the habitus of rearing but will only become aware of them post hoc. The bias is to leave them in so any genetic-endocrine predisposition imposed prenatally can come to be activated with puberty. It is admitted that however there is no good body of clinical data from which the best prognosis can be made in such cases. There are some indications, however, that even without the gonads the adrenals might prod pubertal changes.
  • If a gender change is being considered, have the individual experience a real-life living test. In this way the individual will have first hand experience in how it actually is to live in the other role. Experience has shown that most indeed make the switch permanent but some return to their original sex of rearing. Some, usually as adults, will accept an identity as an intersex and plot their own course.
  • Maintain accurate medical, surgical, and psychotherapy records of all aspects of each case. This will facilitate whatever treatment is needed and assist in future research to enhance management of subsequent intersex cases. These records should be available to the patient.
  • Whenever possible, long term follow-up evaluations, e.g., at 5, 10, 15, and even 20 years of age, should become part of the record.
  • Last, it is believed that information and advice may be provided as much as possible but not to be “authoritarian” in the actions. The postpubertal individual must be allowed time to consider, reflect, discuss and evaluate and then, have the last word in his or her genital modification and gender role and final sex assignment.

CASE STUDY

European Congress of Endocrinology 2008

Berlin, Germany
03 May 2008 – 07 May 2008
European Society of Endocrinology

Hypospadias and micropenis in congenital adrenal hyperplasia: a case study

Sandra Fleischer, Ute S Groß, Hjördis HS Drexler, Achim Wüsthof & Heinrich M Schulte

Endokrinologikum Hamburg, Hamburg, Germany.


Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases with increased adrenal androgens secretion from the adrenal cortex, characterized by simple virilizing and salt wasting forms. Deficiency of 21-hydroxylase, caused by mutations in the 21-hydroxylase gene (CYP21A2) is the most frequent CAH, accounting for more than 90 percent of CAH cases. Deficiency of 3 beta-Hydroxysteroid-Dehydrogenase Type II is caused by mutations in the HSD3B2 gene and accounts for about 1–10 percent of cases of CAH.

Patient: This report is about a 2-year-old patient of Turkish origin referred to our center with clinical finding of penoscrotal hypospadias and micropenis (stretched penile length 1.5 cm). Testicles were palpable bilaterally in the scrotum. Due to initial biochemical and hormonal findings moleculargentic analysis of CYP21A2 gene was already done, showing heterozygous germline mutations p.Val281Leu, p.Leu307fs, p.Gln318Stop and p.Arg356Trp. His parents are cousin-german to each other.

Methods: Genomic DNA was extracted from peripheral blood leukocytes. Coding regions and corresponding exon-intron boundaries of the CYP21A2 gene and the HSD3B2 gene were amplified by PCR and subjected to direct sequencing.

Results: A compound heterozygous state of these mutations was excluded by sequencing analysis ofCYP21A2 genes of both parents (father has no mutation). Further hormonal studies suggested a 3 β-Hydroxysteroid dehydrogenase type II deficiency and justified sequence analysis of the HSD3B2 gene. A novel homozygous germline mutation (p.Trp355Arg) was found, for which both parents are heterozygous carriers.

Conclusion: To judge a case of CAH in the right way it is important to look at all clinical aspects in a differentiated way. Comprehensive (clinical, biochemical, hormonal) analysis should be conducted and approved by moleculargenetic analysis in line with a genetic counseling.


 

REFERENCES

http://www.ukia.co.uk/diamond/diaguide.htm

http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1997-management-of-intersexuality.html

Endocrine Abstracts (2008) 16 P589

References on Ethics and Treatment Options:

  1. ^ David A. Warrell (2005). Oxford textbook of medicine: Sections 18-33. Oxford University Press. pp. 261–. ISBN 978-0-19-856978-7. Retrieved 14 June 2010.
  2. ^ Aubrey Milunsky; Jeff Milunsky (29 January 2010). Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. John Wiley and Sons. pp. 600–. ISBN 978-1-4051-9087-9. Retrieved 14 June 2010.
  3. ^ Richard D. McAnulty, M. Michele Burnette (2006) Sex and sexuality, Volume 1Greenwood Publishing Group, p.165
  4. ^ Elton, Catherine (2010-06-18). “A Prenatal Treatment Raises Questions of Medical Ethics”TIME. Retrieved 2010-07-05.
  5. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (2010-06-29). “Preventing Homosexuality (and Uppity Women) in the Womb?”. Bioethics Forum, a service of the Hastings Center. Retrieved 2010-07-05.
  6. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (30 July 2012). “Prenatal Dexamethasone for Congenital Adrenal Hyperplasia”Journal of Bioethical Inquiry. Retrieved 3 August 2012.
  7. ^ Fernández-Balsells, M.M.; K. Muthusamy, G. Smushkin, et al (2010). “Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: A systematic review and meta-analyses”Clinical Endocrinology 73 (4): 436–444. Retrieved 3 August 2012.
  8. ^ Bongiovanni, Alfred M.; Root, Allen W. (1963). “The Adrenogenital Syndrome”. New England Journal of Medicine 268 (23): 1283.doi:10.1056/NEJM196306062682308.

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion. Congenital forms of hyperinsulinemic hypoglycemia can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years. Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas to protect the brain from damage due to recurrent hypoglycemia.

Types of congenital hyperinsulinism:

1. Transient neonatal hyperinsulinism

2. Focal hyperinsulinism

  • Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15
  • Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15

3. Diffuse hyperinsulinism

a. Autosomal recessive forms

  • i. SUR1 mutations
  • ii. Kir6.2 mutations
  • iii. Congenital disorders of glycosylation

b. Autosomal dominant forms

4. Beckwith-Wiedemann syndrome (thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or IGF2 excess)

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics:

  • a high glucose requirement to correct hypoglycemia and
  • a responsiveness of hypoglycemia to exogenous glucagon.

HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially, with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment.

In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis:

  • pancreatic (18)F-fluoro-L-DOPA PET-CT and
  • molecular analysis.

Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy.

Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable.

The genetics of focal islet-cells hyperplasia associates

  • a paternally inherited mutation of the ABCC8 or
  • the KCNJ11 genes, with
  • a loss of the maternal allele specifically in the hyperplasic islet cells.

The genetics of diffuse isolated HI is heterogeneous and may be

  • recessively inherited (ABCC8 and KCNJ11) or
  • dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH).

Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to

  • potassium channel defect (ABCC8 and KCNJ11),

most of these HI are sensitive to diazoxide.

The main points sum up the management of HI:

  • i) prevention of brain damages by normalizing glycemia and
  • ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Source & References:

http://en.wikipedia.org/wiki/Congenital_hyperinsulinism

http://www.ncbi.nlm.nih.gov/pubmed/20550977

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Hypopituitarism is a partial or complete insufficiency of pituitary hormone secretion that may be derived from pituitary or hypothalamic disease. Onset can be at any time of life. Intrinsic pituitary disease, or any process that disrupts the pituitary stalk or damages the hypothalamus, may produce pituitary hormone deficiency. The clinical presentation of hypopituitarism widely varies, depending on patient age and on the specific hormone deficiencies, which may occur singly or in various combinations. As a general rule, diagnosis of a single pituitary hormone deficiency requires evaluating the other hormone axes.

Etiology

Hypopituitarism has multiple possible etiologies either from congenital or acquired mechanisms. The common endpoint is disrupted synthesis or release of 1 or more pituitary hormones, resulting in clinical manifestations of hypopituitarism. Genetic causes of hypopituitarism are relatively rare. However, research since the late 20th century has brought considerable advances in the understanding of the various genetic causes of congenital hypopituitarism. Inheritance patterns may be autosomal recessive, autosomal dominant, or X-linked recessive. The phenotype and severity of clinical findings in congenital hypopituitarism are determined by the specific genetic mutation. Causes of hypopituitarism can be divided into categories of congenital and acquired causes.

Congenital causes of hypopituitarism include the following:

  • Perinatal insults (eg, traumatic delivery, birth asphyxia)
  • Interrupted pituitary stalk
  • Absent or ectopic neurohypophysis
  • Pallister-Hall syndrome

Multiple Pituitary Hormone Deficiency is rare in childhood, with a possible incidence of fewer than 3 cases per million people per year. The most common pituitary hormone deficiency, growth hormone deficiency (GHD), is much more frequent; a US study reported a prevalence of 1 case in 3480 children.A 2001 population study in adults in Spain estimated the annual incidence of hypopituitarism at 4.2 cases per 100,000 population. Because hypopituitarism has congenital and acquired forms, the disease can occur in neonates, infants, children, adolescents, and adults.

Prognosis

With appropriate treatment, the overall prognosis in hypopituitarism is very good. Sequels from episodes of severe hypoglycemia, hypernatremia, or adrenal crises are among potential complications. Long-term complications include short stature, osteoporosis, increased cardiovascular morbidity/mortality, and infertility. Previous findings of increased cardiovascular morbidity and decreased life expectancy in adults with hypopituitarism were thought to be largely secondary to untreated GHD.

Mortality/morbidity

Morbidity and mortality statistics generally cannot be viewed in isolation but must instead be related to the underlying cause of hypopituitarism. For example, morbidity and mortality are minimal in the context of idiopathic GHD compared with hypopituitarism caused by craniopharyngioma. Recognition of pituitary insufficiency and appropriate hormone replacement (including stress doses of hydrocortisone, when indicated) are essential for the avoidance of unnecessary morbidity and mortality. Clinical manifestations of isolated or multiple deficiencies in pituitary hormones (anterior and/or posterior) can result in significant sequelae that include any of the following:

  • Hypoglycemia – Can cause convulsions; persistent, severe hypoglycemia can cause permanent CNS injury.
  • Adrenal crisis – Can occur during periods of significant stress, from ACTH or CRH deficiency; symptoms include profound hypotension, severe shock, and death.
  • Short stature – Can have significant psychosocial consequences.
  • Hypogonadism and impaired fertility – From gonadotropin deficiency
  • Osteoporosis – Results in increased fracture risk

GHD is believed to be an important contributing factor to morbidity and mortality associated with hypopituitarism. In a 2008 study, childhood onset GHD was associated with an increased hazard ratio for morbidity of greater than 3.0 for males and females. Causes of morbidity and mortality are multifactorial and relate to the specific cause of hypopituitarism, as well as to the degree of pituitary hormone deficiency.

Source References:

http://tbccn.org/CCJRoot/v9n3/pdf/212.pdf

http://emedicine.medscape.com/article/922410-overview

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