Noonan Syndrome

Noonan Syndrome

  • webbed neck syndrome
  • male Turner syndrome
  • female pseudo-Turner syndrome

Jacqueline Noonan, paediatrician and heart specialist in 1963, published a report on a small group of patients with typical facies, congenital heart defect, and some clinical features similar to Turner syndrome, but with normal chromosomes. Its after her that this syndrome has been named.

Noonan syndrome is inherited as an autosomal dominant condition. This means that the Noonan gene is on a non-sex (autosomal) chromosome and is transmitted from parent with a 50% probability to child. Although one dose of the Noonan gene is enough to cause the syndrome. A gene for Noonan syndrome (NS1) has been mapped to chromosome number 12. There are several different Noonan genes.

The frequency of the Noonan syndrome is estimated to be between 1:1,000 and 1:2,500 in the general population

Main features of this syndrome are:

  • Pulmonary Stenosis
  • Short stature after birth
  • Webbing of Neck
  • Caved in Chest Bones
  • In boys, Testes that do not descend into the scrotum.

Other possible heart defects are hypertrophic cardiomyopathy (thickened heart muscle), atrial septum defect (hole in the wall separating the anterior heart chambers), ventricular septum defect(hole in the wall separating the main heart chambers), septal hypertrophy or a combination of all these defects.

Other Facial features that may be present in this syndrome are:

  • Drooping of eyelids.
  • Downwards slanting eyes with arched eyebrows
  • Extra skin fold at the inner angle of the eyes.
  • Increased distance between the eyes.
  • Broad forehead
  • Very Blue or blue green eyes
  • Curly hair
  • Flat broad root of the nose.
  • Short broad neck with skin folds
  • Many pigmented birth marks

Variations occur in the facial features and they change with the age. As the child grows, the face gradually becomes more normal, often more triangular with a high forehead.

Other features of this syndrome

  • The birth length and weight of children with Noonan syndrome are often normal. The increase in height in both boys and girls is less than normal throughout the whole growing period.
  • On an average, puberty is delayed by about two years in both sexes.
  • During the first years of life the children may have great feeding and nutrition problems and frequent respiratory tract infections.
  • Only a few children with Noonan syndrome are seriously handicapped. Delayed motor development and speech may be seen in about 25% of the children.
  • Studies have shown that these children’s IQ was within normal limits, though in most cases in the lower range of normal. Mental retardation in approx. 35 %
  • Many of those with Noonan syndrome have a form of visual disturbance, squinting, near sight, or long sight, which may necessitate use of spectacles. The visual disturbance is usually mild.
  • A mild type of hearing impairment has been reported.
  • Children with Noonan syndrome often have dental problems. 1/3 of them have wrongly positioned teeth. The teeth often appear late and in an abnormal order.
  • Repeated attacks of epilepsy have been described in a few cases
  • Reduced fertility in men. Women’s fertility is normal.

Human Genome

Human Genome

On Monday 26 June 2000, after more than a decade of effort, a working draft of the human genome was presented to the humanity. This day would be remembered as the day when humankind learned about the set of genetic instructions which governs the assembly and fuction of human beings.

The scale of this triumph of biological science is awesome.

  • The 24 different human chromosomes may be too small for the eye to see, but each set contains 3.1 billion base pairs: a code written in 3.1 billion “letters”. This amount of data is equivalent to the contents of 200 telephone directories, each 500 pages long. It has been estimated that it would take over nine years to read aloud this data.
  • If all the DNA in the human body were put end to end, it would reach to the sun and back more than 600 times.
  • There are 20 different building blocks (amino acids ) used in an array of combinations to produce proteins as different as keratin in the hair and haemoglobin in the blood.
  • The vast majority of the DNA (97 % ) in human genome has no known function.
  • Between humans the DNA differs by only 0.2 %.
  • Human DNA is 98 % identical to chimpanzee.
  • Scientists estimate that there are 300,000 spots in the human genetic code where individual differences can exist.

Reading Human genome code took the combined efforts of thousands of researchers, and countless hours of work by hundreds of state-of-the-art robotic sequencing machines humming quietly around the clock in pristine laboratories. Each machine prepares DNA samples, runs them through electrophoresis gels, and reads off the results into a database, only requiring the help of a human once every 24 hours.

The public Human Genome Project took blood and sperm samples from a dozen anonymous donors and combined them. The project’s commercial rival, Celera Genomics, put an ad in The Washington Post, selected 30 men and women from a variety of ethnic backgrounds and used six of them.

Estimated number of genes:
Humans & mice – 60,000 to 100,000
Roundworm – 19,000
Yeast – 6,000

October 16, 2002
Researchers have come up with some new findings. That the genome has revealed  that the human chromosome carries only about 30,000 genes, twice the number of a fruit fly, 10,000 more than a roundworm, and only a few hundred more than a mouse. Originally scientists expected as many as 140,000, which means the question of how genes actually work is now an even bigger mystery. The genome also reveals that many human genes originate from microbes. This raises questions about human evolution.

In future:

  • Doctors may treat you for conditions such as cancer and heart disease even before they appear. There may be fundamental shift towards preventive medicine.
  • A routine check-up in future will perhaps involve giving a sample of blood from which your DNA will be extracted and screened to determine your risk of developing various diseases.
  • We already know the genes that cause many rare, single-gene disorders, but in future you could be screened for common diseases that appear in adulthood, such as type II diabetes, heart disease and cancer, and perhaps even complex mental disorders such as schizophrenia and depression. Because these diseases have many contributory factors, both genetic and environmental, the test results will give a percentage risk rather than a definite yes or no.
  • Doctors may also use gene screening to discover which drugs best suit you. Our genes determine whether different drugs will work well or cause side effects. For example, Alzheimer’s patients with a gene variant called ApoE 4 are much less likely to benefit from a drug called tacrine than other patients.
  • The insurance agencies making use of genetic information is a possibility.
A single gene may play a role in the development of cancer and a number of age-related diseases, including arthritis, hardening of the arteries and Alzheimer’s disease, according to new study findings.
Gene Therapy
Genetic disorders
Genome Sequencing helps diagnosing rare disorder

Gene Therapy

Gene Therapy

Gene therapy is a newer approach to treating diseases based on modifying a person’s genes toward a therapeutic goal. Gene therapy has been targeted towards treating lethal and disabling diseases. It also has potential of preventing diseases. This method of treatment is still in its infancy.
It can be said that the gene that we inherit from our parents influence practically every disease. A composite of approximately 150,000 individual genes constitutes a human being. Several years ago, an international effort was launched to identify every single human gene. This effort, called the Human Genome Project. Variation in the structure of a person’s genes collectively helps define us as individuals such as how tall we are to what color our eyes are supposed to have. Some of this genetic ‘miscalculations’ unfortunately leads to the development of disease. The genetics of many diseases are passed from one generation to the next by inheriting a single gene. An example is Huntingdon’s disease. Many other diseases and traits are influenced by a collection of genes.
The premise of gene therapy is to treat the disease at its root. There are two types of Gene Theapy. Somatic Gene Therapy and  Germline Gene Therapy.
Somatic gene therapy involves the manipulation of gene expression in cells that will be corrective to the patient but not inherited to the next generation.
Germline gene therapy, this involves the genetic modification of germ cells that will pass the change on to the next generation.
It is the Somatic Gene therapy that is being mainly investigated throughout the world. The work on Germline gene therapy is restricted due to technical and ethical reasons.
To deliver genetic material to the appropriate cells of the patient in a way that is specific, efficient and safe, gene delivery vehicles called vectors have been created. The vectors being used are modified and attenuated viruses. The virus is modified in such a way that its disease causing component is removed and in its place gene are inserted. Synthetic vectors are also being used formed of complexes of DNA, Protein and Lipids.
The first human trials of Gene therapy began in 1990. Many types of diseases are currently being investigated as candidates for gene therapy including cardiovascular diseases, cholesterol lowering therapy, infectious diseases such as AIDS, and cancer.
Gene therapy can be used not only in treating genetic diseases but also to deliver specific proteins. By placing genes in laboratory-cultured organisms that produce the proteins coded by those genes. Examples of such manufactured proteins include insulin, growth hormone, and erythropoietin, all of which must be injected frequently into the patient.
In hemophilia treatments, a gene-carrying vector could be injected into a muscle, prompting the muscle cells to produce Factor IX and thus prevent bleeding. This method would end the need for injections of Factor IX — a derivative of pooled blood products and a potential source of HIV and hepatitis infection. In gene therapies such as these, the introduced gene is always “on” so the protein is always being produced, possibly even in instances when it isn’t needed.

First human chromosome mapped

For the first time, scientists have mapped virtually an entire human chromosome, one of the chains of molecules that bear the genetic recipe for human life. The achievement was announced on Wednesday 1st Dec ’99. It was an important step for the $3 billion Human Genome Project, which is attempting to detail the tens of thousands of genes that carry instructions for everything in a human from brain function to hair color to foot size.
This is probably the most important scientific effort that mankind has ever mounted. That includes splitting the atom and going to the moon. In laying out the chemical instructions for life, scientists believe they are in the early stages of revolutionizing the study of human development and medicine. Already, researchers have begun testing several biological therapies that replace faulty genes or correct their misfirings to make cells work correctly. Such therapies, if they can be made reliable, would bring a more precise way to treat diseases without the sometimes debilitating side effects of conventional drugs.
The defects in the genes along the chromosome contribute to heart defects, immune system disorders, cancers, schizophrenia and mental retardation.

The human genetic pattern, or genome, is a biological map laying out the sequence of 3 billion pairs of chemicals that make up the DNA in each cell. All human DNA is contained within 23 pairs of chromosomes.

Genes are arrayed along chromosomes, the rod-shaped bodies inside the nucleus of a cell. Proteins and other compounds carry out the instructions of genes. Inside the chromosomes, genetic material is linked along tightly coiled strands of the master molecule DNA, which twists like a spiral ladder. Each rung is built with pairs of four chemical bases ordered in different numbers and combinations to form genes.

Mapping a gene is only an early step in understanding the gene’s function and how it might contribute to a particular disease.

Human Genome 
Genome Sequencing helps diagnosing rare disorder
Genome Editing

Genetic counselling

Genetic counselling

The cells in our body, throughout their lives, duplicate themselves to create new tissue. The 23 pairs of chromosomes in a cell also double to 46. But sometimes the pattern of duplication is disturbed. Instead of merely duplicating a chromosome may triplicate or even break, causing various birth defects. These disorders can be passed to future generations.

Genetic counselling is a way to screening high risk populations for various diseases like families prone to cancers, thalassaemia and many genetically transferable diseases The geneticists assess the potential risk of passing on the disorder to future generations. This helps the parents to be to take informed decision about terminating a pregnancy and avoiding the trauma of having a disabled child.

Many couples are faced with difficult situations regarding the possibility of a new born being a physically disabled child or the child may be suffering from a very troublesome illness like Thalassaemia. Some couples have a child in their family already suffering from thalassaemia and the prospects of having another child with same illness are devastating. A thalassaemic child may have to undergo repeated blood transfusions. Some may need it fortnightly.

Genetics has come a long way to solve many of such problems. Tests can be conducted to find out if the unborn child carries a thalassaemia gene. Procedures have been developed by which artificially fertilised healthy embryo can be implanted in the uterus of elderly women anxious to have a healthy child. There are also methods by which genetic mapping can be done of a person to find out if he or she is carrying any faulty chromosome.
Some of the methods employed are

Polymerase Chain Reaction (PCR): Is a procedure that can reveal whether an unborn child carries a thalassaemia gene. This procedure is done mainly to detect minute abnormalities of the genes that cause diseases like thalassaemia, cystic fibrosis, haemophilia and muscular dystrophy.

Pre-implantation Genetic diagnosis (PGD): This procedure can create and select an artificially fertilised healthy embryo and implant it in the uterus, and thus ensuring that the high risk couple has a normal baby.

Karyotyping : is done to map the genetic makeup of a person to detect any faulty sex chromosome. Karyotyping is very helpful in showing up chromosomal abnormalities that cause severe physical disabilities like Tisomys – Trisomy 21 causes Down’s Syndrome, Trisomy 18 causes limb deformities and microcephaly, Trisomy 13 gives a cleft palate.

Genetic disorders

Congenital Generalized Lipodystrophy

Congenital Generalized Lipodystrophy

Berardinelli-Seip Syndrome

Congenital Generalized Lipodystrophy is a rare genetic disease. It is characterized by near complete absence of body fat. It is inherited as an autosomal recessive disorder. It is a disease involving the adipose tissue (fat tissue) of the body.

Parents are carriers of the genes but are not affected. There is a 25% chance of transmission of both defective genes to the affected children. The ratio of affected to unaffected children is 1:4.

Clinical features

  • The diagnosis is evident at birth or immediately afterwards. These infants look very muscular due to the absence of fat. Nearly the entire body is affected, only the palms, soles and scalp are spared.
  • These patients also have accelerated growth during their childhood and have a voracious appetite.
  • The onset of diabetes is usually during the pubertal years and requires high dose of insulin to control the blood glucose levels.
  • They have Severe insulin resistance; high serum insulin and triglyceride levels and low levels of high-density lipoprotein (HDL) cholesterol.
  • Also have acanthosis nigricans (dark velvety pigmentation of the skin) in the axilla, neck or groin.
  • Enlarged hands, feet and prominent mandible (acromegaloid features), umbilical hernia .
  • They have lytic lesions (look like bone is eaten-up on X-rays) in the long bones of the body such as the humerus, femur.
  • Females present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles and polycystic ovaries
  • A gene for CGL has been identified on the long arm of chromosome 9 (9q34).
Acquired Generalized Lipodystrophy
Familial Partial Lipodystrophy