Genetic testing is a method of genetic diagnosis to check for the susceptibility to hereditary diseases and can also be used to establish the ancestry of any person. Genetic testing studies the chromosome, breaking it to individual genes. In a broader sense, it can be used as a biochemical test for scrutinizing the existence and nonexistence of main proteins that hint abnormalities of certain genes. Genetic testing studies the abnormality in the chromosomes, genes or proteins. It can be used to find out whether a particular genetic condition is developing and it's chances of being passed over to the future generations.
The most widely used type of genetic testing is newborn screening. Genetic testing during pregnancies is called as prenatal genetic testing and is performed during pregnancy to screen or identify birth defects. This provides ample information on the developing fetus both for the parents and the physician. Amniocentesis and chorionic villus sampling is the common diagnostic test performed to diagnose any defect in the fetus. These diagnostic tests are ordered for if the triple test (AFP test, hCG blood test, and UE3) returns abnormal results.
Osteogenesis imperfecta or OI, also known as brittle bone disease, is a genetic disorder that is characterized by weak and fragile bones that break easily. Osteogenesis imperfecta is caused by a genetic defect that disables the body to make strong bones. A person may experience occasional fractures or may have multiple fractures throughout life depending upon the severity of Osteogenesis imperfecta present. Apart from fragile bones, people with OI suffer from teeth problems - Dentinogenesis Imperfecta, hearing loss, muscle weakness, loose joints (joint laxity) and skeletal malformations.
Causes of OI
Osteogenesis imperfecta is either inherited from a parent who has the defective gene or could be a result of new mutations. Due to the defective gene, an important protein substance called type I collagen is not produced in the body. This protein plays an important role in forming connective tissues in bones and also helps in forming ligaments, teeth and the white outer tissue of the eyeballs (sclera). Due to poor production of the protein, bones become brittle and fragile and tend to break easily. Most of the mutations in OI exist in the two type I collagen genes, COL1A1 and COL1A2 and account for almost all the forms of OI.
Classification of Osteogenesis imperfecta
Depending upon the severity of the Osteogenesis imperfecta, the condition is divided into type 1, type 2, type 3, type 4. These types are classified mostly by fracture frequency and by characteristic features. Recently, research has identified three more additional variations to Osteogenesis imperfecta known as type 5, 6 and 7.
Type 1 Osteogenesis imperfecta is the mildest and the most common form of OI. More than 50% patients suffer from Type 1 Osteogenesis imperfecta. In this type, though body produces normal type I collagen but only half the normal quantity. People with Type 1 OI may experience fewer fractures, and most often the condition may go unnoticed for several years after their birth.
Type 2 Is the most severe form of Osteogenesis imperfecta often resulting in bone deformities in the child. Type 2 OI normally turns out to be fatal with the production of very little or poor quality collagen being produced in the body. Infants with type 2 OI are born with fragile rib cage and underdeveloped lungs. They usually die either in the womb or soon after birth.
Osteogenesis imperfecta type III is severely progressive type associated with symptoms like short stature, a triangular face, severe scoliosis, grayish sclera, and Dentinogenesis imperfecta (impaired and irregular teeth with yellow-blue tinge). Infants with type 3 OI have fractures at the time of birth itself, and few infants reveal a fractured and eventually healed bones in the womb itself.
Type 4 Osteogenesis imperfecta can range from very mild to severe form often resulting in growth retardation in children. A child with type 4 OI is short with bow shaped legs. Symptoms like tinted sclerae (white of the eye) and dental deformities may also be present at the time of the birth. Child normally suffers from Long bone fractures, vertebral compression, scoliosis, and ligament laxity with type 4 OI.
Type 4 also has two sub types called type 5 and type 6 OI. Though clinically they resemble type 4, types 5 and 6 have unique patterns to the bones. Type 5 exhibits features like ossification of interosseous membrane of the forearm with radial head dislocation, large callus formation and an abnormal histopathological pattern. Type 6 will have elevated alkaline phosphatase and blue-white sclerae.
Most severe forms are diagnosed before birth itself. Ultrasound scanning during second trimester may reveal deformity of limbs, abnormally short fetus, irregular skull shape, lack of mineralizations and narrow chest cavity. Few cases are diagnosed soon after the birth and mild type of OI is found out much later in life when such individuals suffer from repeated fractures. However, the following diagnostic methods are used to assess the condition.
Since Osteogenesis imperfecta is a genetic condition, it does not have a cure. Patient will be treated symptomatically and will be aided with external tools to provide maximum possible mobility. Efforts are also taken to improve muscle strength and boost the bone mass in the patient through physical therapy. Professionally designed exercise programmes are highly beneficial and play an important role in treating the patients suffering from OI. Patient may also be prescribed required nutritional supplements like calcium, and vitamin D along with physical therapy. Few suitable candidates are also treated with surgical procedure called intramedullary rod surgery wherein metal rods are inserted through the length of the long bones to support and strengthen them.
Of late, Bisphosphonates drugs are being used in treating Osteogenesis imperfecta. Bisphosphonates are used to decrease the amount of bone resorption. It also helps in preventing fractures and improve person's functional mobility. There is also research being done to understand the role of gene therapy in treating Osteogenesis imperfecta.
Prognosis of Osteogenesis imperfecta depends upon the severity of the conditions. Despite bone deformity, restricted activity, and short stature, often patients with OI lead productive and near to normal lives.
A rare hormonal condition characterized by delayed or absence of puberty and an impaired sense of smell is Kallmann syndrome. This belongs to a larger group of conditions known as hypogonadotrophic hypogonadism. This condition is usually characterized by a failure to start or fully complete puberty. However hypogonadotrophic hypogonadism can be treated successfully by means of specialized hormone replacement therapy.
It is estimated that this syndrome affects 1 in 10,000 to 86,000 people and occurs more often in males rather than in females. Kallmann Syndrome 1 is the most common form of this condition. It was Franz Kallmann, an American scientist who first published a paper in 1914 about this syndrome. Therefore this genetic condition is named after him.
Characteristics of Kallmann Syndrome
Males with hypogonadotrophic hypogonadism are born with unusually small penis and undescended testes. Whereas, females affected, usually do not begin menstruating at puberty and have little or no breast development at all. In some women, puberty is either incomplete or delayed. In short, at puberty those affected do not develop secondary sexual characteristics.
In Kallmann syndrome, the sense of smell is particularly diminished or completely absent. This feature indeed distinguishes this syndrome from most other forms of hypogonadotrophic hypogonadism.
The significant aspect here is that most patients are not aware of this inability to detect odors until they are diagnosed. Some points to remember:
Inability to smell strong warning smells such as smoke or gas.
Inability to smell caustic products such as bleach.
Inability to smell rotten/spoilt food.
Personal hygiene, body odor and clothes.
Since the sense of smell is also linked to the sense of taste, some foods will not taste the same as with other people.
Signs and Symptoms
Kallmann Syndrome, even within the same family may vary in its features. Some additional symptoms and signs may include failure of one kidney to develop, a cleft lip with or without an opening in the roof of the mouth or a cleft palate, abnormal eye movements, hearing loss and abnormalities in tooth development.
In some affected persons, the movements of one hand are mirrored by the other hand - Bimanual Synkinesis. This can make it difficult to undertake tasks that require the hands to move separately such as playing a musical instrument. Kallmann syndrome has types designated from 1 through 4 distinguished by their genetic cause. The four types are identified as four forms of Kallmann syndrome, each characterized by an impaired sense of smell. Additional features of cleft palate occur only in types 1 and 2.
Kallmann syndrome and other related conditions are congenital in nature and are present from birth. Their genetic basis may not be fully understood and this syndrome can be inherited through the generations although it is difficult for the doctor to predict if this will occur.
The genetic factor: Certain mutations in the KAL1, FGFR1, PROKR2, and PROK2 genes cause Kallmann syndrome. Mutations in FGFR1 gene causes syndrome type 2 and mutations in PROKR2 and PROK2 cause Kallmann syndromes types 3 and 4 respectively.
These genes seem to play a role in the development of the brain much before birth. They are involved in the formation and movement of a group of nerve cells that are specialized in olfactory or smell process. The mutations KAL1, FGFR1, PROKR2, and PROK2 genes which play a role in the migration of neurons that produce a hormone called GnRH – Gonodotropin releasing hormone that controls several other hormones that direct sexual development before birth and during puberty. These hormones are necessary for the normal functioning of the ovaries in women and testes in men. These mutations disrupt the olfactory nerve cells and GnRH producing nerve cells in the brain. However these conditions and features vary among individuals and thus additional genetic and environmental factors may be involved.
Without proper treatment, the affected female is likely to face infertility and have an increased risk of developing osteoporosis or brittle bones. However, with correct diagnosis and treatment, fertility can be achieved in many cases and risk of osteoporosis decreased.
Following clinical examination, certain biochemical parameters and various imaging tests are done to confirm the diagnosis. As this is a genetic condition, testing for various genetic forms of this disease may also assist in making the diagnosis.
Initially hormone replacement therapy - testosterone in males and estrogen and progesterone in females is used to help induce secondary sexual characteristics.
Once pubertal maturation happens, for fertility either injection of pituitary hormones – gonadotropins, LH and FSH and in some instances therapy with synthetic peptide, GnRH is given. Deficiency of these hormones causes syndromes, and these are required to induce the sex organs to make sperm in males and eggs in females.
In females, the steps taken may vary depending upon individuals and the desired outcome. In premenopausal women, a step-by-step increase in estrogen dosage is given. A bone scan is done to assess the bone age. Without the presence of estrogen, the bone age will be behind that normally seen at that chronological age. The aim is to match the estrogen dosage to the bone age such that the development of bone can be enhanced. The doctor usually monitors the stage of treatment very closely.
Specialist fertility treatments are available and these can induce a certain level of fertility. The aim is to produce hormones by the pituitary and hypothalamus glands and induce natural production of sex hormones. Results can take 6 to 18 months but it is possible to induce fertility in some cases.
There are various drugs available which are usually self-injected twice or thrice a week over a period of at least six weeks. To combat the risk of osteoporosis, it becomes necessary to take tablets that reduce the risk. These tablets help increase the calcium uptake by the bones to strengthen them. However, medication will not eliminate the risk of osteoporosis.
Early diagnosis, education, personal outlook and support from family and friends can help reduce the problems surrounding this syndrome. Kallmann syndrome is usually lifelong in nature and about 10-15% of patients may experience recovery of hormonal system.
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Bibliography / Reference
Collection of Pages - Last revised Date: January 27, 2023