Other Genetic Syndromes

Question 1

What is achondroplasia?

Answer 1

It is a form of short limb dwarfism which is caused by mutations in the FGFR3 gene.

Inheritance is autosomal dominant. Although many cases are due to de novo mutations in the FGFR3 gene.

Question 2

What is the clinical presentation of those with achondroplasia?

Answer 2

Short stature with short limb length.
Macrocephaly.

Normal intelligence and life expectancy.

More prone to developing spinal abnormalities:

• Lordiosis
• Kyphosis
• Spinal stenosis

Question 3

What is Noonan’s syndrome?

Answer 3

It is an autosomal dominant disorder characterised by:

• dysmorphic features including short stature
• congenital cardiac defect
• bleeding (repeated nosebleeds/menorrhagia)
• chest wall deformities
• undescended testicles

Question 4

What are the dysmorphic features of Noonan’s?

Answer 4

General:
Short stature

Face:
Low hair line
Wide spaced eyes
Low set ears
Small jaw

Other:
Webbed neck
Chest wall deformities

Question 5

What is Fragile X syndrome?

Answer 5

It is an X linked dominant condition (therefore women with one affected gene will be affected).

Which is characterised by dysmorphic features, learning difficulties and developmental delay.

Men have a more severe phenotypic presentation.

Question 6

What is Marfan’s syndrome and what are the clinical features?

Answer 6

It is an autosomal dominant connective tissue disorder. However, 25% have de novo mutations

It is characterised by:
Tall stature and thin
Arm span greater than their height
Hyper-flexibility 
Pigeon chest
Arrhythmias
Scoliosis
High arched palate
Crowded teeth
Nearsightedness
Flat feet
Lens subluxation

The main clinical features are:

• Ectopia lentis (dislocated lenses in the eyes)
• Aortic aneurysm/dissections/regurg
• Mitral valve prolapse
• Chest wall deformities

Question 7

What is phenylketonuria (PKU)?

Answer 7

It is an autosomal recessive disease in which there are high levels of phenylalanine in the blood.

Deficiency in phenylalanine hydroxylase that normally converts phenylalanine to tyrosine.

Picked up in heel prick test

If not treated this can cause:

• developmental delay
• learning difficulties
• seizures
• small head size
• hyperactivity

Treat with diet low in phenylalanine

It is a spectrum of disorders ranging from severe classical PKU and mild diseases.

Phenylalanine can also act as a teratogen so women with PKU often have babies with learning difficulties.

Question 8

What is Rett’s syndrome?

Answer 8

It is a de novo genetic disorder which occurs in females.

It is characterised by normal development unto 6-18months of age followed by developmental regression in language and motor domains.

Question 9

What is Prader-Willi syndrome?

Answer 9

It is a genetic disorder caused by a deletion on the long arm of the paternal chromosome 15.

It is characterised by:

• Underdeveloped genitalia causing infertility
• Unsatiable appetite leading to obesity
• Learning difficulties
• Behavioural problems such as temper tantrums

Question 10

What is Angelman’s syndrome?

Answer 10

It is a genetic disorder caused by a deletion on the long arm of the maternal chromosome 15.

It is characterised by:

• delayed development
• learning difficulties
• severe speech impairment
• ataxia
• microcephaly
• seizures

Those with angle mans often have a happy excitable demeanour.

Question 11

What is Williams syndrome?

Answer 11

It is a genetic disorder which usually occurs due de novo mutations.

It is characterised by:

• mild to moderate intellectual disability
• friendly personality characteristics
• dysmorphic features - elvin facies
• cardiac defects (supravalvular aortic stenosis)

Question 12

How does fragile X present?

Answer 12

Elongated face, prominent jaw, and large ears.
Delayed milestones
Mental retardation
Macrocephaly

Question 13

The mutation that causes Marfan’s?

Answer 13

FBN1 - fibrillin gene

Question 14

Marfan’s investigations

Answer 14

Echo, ECG, eye exam, x-ray, DNA study

Question 15

Angleman’s facies

Answer 15

Prominent chin, deep-set eyes, abnormally wide mouth, protruding tongue, wide-spaced teeth and brachycephaly

Question 16

What is Treacher-Collins syndrome?

Answer 16

Malformation of facial bones, including cochlea and ossicles.

Can cause breathing, feeding, hearing and sight difficulties.

Treated with surgery, cochlear implants and orthodotics.

Question 17

Klinefelter syndrome presentation

Answer 17

in babies and toddlers – learning to sit up, crawl, walk and talk later than usual, being quieter and more passive than usual
in childhood – shyness and low self-confidence, problems with reading, writing, spelling and paying attention, mild dyslexia or dyspraxia, low energy levels, and difficulty socialising or expressing feelings
in teenagers – growing taller than expected for the family (with long arms and legs), broad hips, poor muscle tone and slower than usual muscle growth, reduced facial and body hair that starts growing later than usual, a small penis and testicles, and enlarged breasts (gynaecomastia)
in adulthood – inability to have children naturally (infertility) and a low sex drive, in addition to the physical characteristics mentioned above

Question 18

Klinefelter syndrome pathology

Answer 18

Extra X chromosome so baby has XXY meaning it is a male

Question 19

Complications of kleinfelter syndrome

Answer 19

type 2 diabetes
weak and fragile bones (osteoporosis)
cardiovascular disease and blood clots
autoimmune disorders (where the immune system mistakenly attacks the body), such as lupus
an underactive thyroid gland (hypothyroidism)
anxiety, learning difficulties and depression – although intelligence is usually unaffected
male breast cancer – although this is very rare

Question 20

Treatment of kleinfelter syndrome?

Answer 20

testosterone replacement therapy
speech and language therapy during childhood to help with speech development
educational and behavioural support at school to help with any learning difficulties or behaviour problems
occupational therapy to help with any co-ordination problems associated with dyspraxia
physiotherapy to help build muscle and increase strength
psychological support for any mental health issues
fertility treatment – options include artificial insemination using donor sperm or possibly intracytoplasmic sperm injection (ICSI), where sperm removed during a small operation are used to fertilise an egg in a laboratory
breast reduction surgery to remove excess breast tissue

Question 21

What is Crigler-Najar syndrome?

Answer 21

Crigler-Najjar syndrome is a rare genetic disorder characterized by an inability to properly convert and clear bilirubin from the body.

Question 22

Presentation of crigler-najjar syndrome

Answer 22

Early jaundice with risk of kernicterus

Question 23

What is alport syndrome?

Answer 23

Alport syndrome is a disease that damages the tiny blood vessels in your kidneys. It can lead to kidney disease and kidney failure. It can also cause hearing loss and problems within the eyes. Alport syndrome causes damage to your kidneys by attacking the glomeruli.

Question 24

What genes do Alpot syndrome affect?

Answer 24

Collagen genes

Question 25

Presentation of alport syndrome

Answer 25

Blood in the urine (hematuria), the most common and earliest sign of Alport syndrome
Protein in the urine (proteinuria)
High blood pressure (hypertension)
Swelling in the legs, ankle, feet and around the eyes (called edema)

Question 26

Diagnosis of alport syndrome

Answer 26

Urine test: A urine test will help find protein and blood in your urine.
Blood test: A blood test will help find levels of protein, and wastes in your blood.
Glomerular filtration rate (GFR): A blood test will be done to know how well your kidneys are filtering the wastes from your body.
Kidney biopsy: In this test, a tiny piece of your kidney is removed with a special needle, and looked at under a microscope.
Hearing test: A hearing test will be done to see if your hearing has been affected.
Vision test: A vision test will be done to see if you vision has been affected.
Genetic test: This can help confirm the diagnosis and determine the genetic type of Alport syndrome you may have.

Question 27

Treatetment of alport syndrome

Answer 27

ACE inhibitor or ARB medicines (medications to control high blood pressure)
Diuretics (water pills)
Limit sodium (salt) in your diet

Question 28

Lesch Nyan syndrome

Answer 28

Lesch Nyhan syndrome is a condition characterized by neurological and behavioral abnormalities and the overproduction of uric acid in the body. It occurs almost exclusively in males. Signs and symptoms may include inflammatory arthritis (gout), kidney stones, bladder stones, and moderate cognitive disability. Nervous system and behavioral disturbances also occur, such as involuntary muscle movements and self injury (including biting and head banging). People with Lesch Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair.[1][2] Lesch Nyhan syndrome is caused by changes (mutations) in the HPRT1 gene and is inherited in an X-linked recessive manner.[1] Treatment is symptomatic and supportive. Affected people often do not survive past the first or second decade of life due to renal failure.[2]

Question 29

22q11 (DiGeorge) presentation

Answer 29

CATCH 22

Cardiac defects
Abnormal facies
Thymic hyperplasia
Cleft palate
Hypocalceamia
22q11 deletion

learning and behaviour problems – including delays in learning to walk or talk, learning disabilities and problems such as attention deficit hyperactivity disorder (ADHD) or autism
speech and hearing problems – including temporary hearing loss due to frequent ear infections, being slow to start talking and having a “nasal-sounding” voice
mouth and feeding problems – including a gap in the top of the mouth or lip (cleft lip or palate), difficulty feeding and sometimes bringing food back up through the nose
heart problems – some children and adults have heart defects from birth (congenital heart disease)
hormone problems – an underactive parathyroid gland (hypoparathyroidism) is common and can lead to problems such as shaking (tremors) and seizures (fits)
Other possible problems include:

a higher risk of getting infections – such as ear infections, oral thrush and chest infections – because the immune system (the body’s natural defence against illness) is weaker than normal
bone, muscle and joint problems – including leg pains that keep coming back, an unusually curved spine (scoliosis) and rheumatoid arthritis
short stature – children and adults may be shorter than average
mental health problems – adults are more likely to have problems such as schizophrenia and anxiety disorders

Question 30

Treatment of 22q11 deletion syndrome

Answer 30

regular hearing tests, blood tests, heart scans and measurements of their height and weight
an assessment of their development and learning ability before starting school – if your child has a learning disability, they may need extra support at a mainstream school, or they may benefit from attending a special school (read more about education for children with learning disabilities)
speech therapy to help with speech problems and dietary changes (or sometimes a temporary feeding tube) to help with feeding problems
physiotherapy for problems with strength and movement
treatment from a podiatrist for foot and leg problems, and devices such as shoe inserts (orthoses) for leg pain
surgery for more severe problems – for example, surgery to repair heart defects or an operation to repair a cleft palate

Question 31

Costello syndrome presentation

Answer 31

High birth weight, show poor sucking ability, have swallowing difficulties, and fail to grow and gain weight at the expected rate (failure to thrive). Growth delay after birth typically results in short stature during childhood and adulthood. Affected children may have developmental delay or mild to moderate intellectual disability. In some individuals, speech development and/or the ability to walk is significantly delayed. Children with Costello syndrome generally have warm, sociable personalities.

Individuals with Costello syndrome typically have loose skin (cutis laxa) on the neck, palms, fingers, and soles. The skin in these areas may lack elasticity and hang loosely; in addition, the skin may appear wrinkled and thickened. In some cases, certain areas of the skin may become unusually dark (hyperpigmentation). In addition, most patients with this disorder develop dry hardened patches of skin (hyperkeratosis) with unusually deep creases on the palms and soles. Some affected individuals may also have skeletal abnormalities such as dislocated hips, abnormally flexible (hyperextensible) joints of the fingers, wrists bent toward the little finger (ulnar deviation) and/or unusual tightening of the fibrous cords on the back of the heels (Achilles tendon). Additional skeletal abnormalities include side-to-side curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and reduced range of motion in the shoulder and elbows.

Children with Costello syndrome usually devlelop papillomata around the mouth and nostrils. Papillomata may develop as early as two years of age or at older ages. In some cases, these wart-like (verrucal) lesions may be found near the anus. Papillomata usually become more apparent with age. Other benign tumors have also been reported.

Children with Costello syndrome have a distinctive facial appearance. Characteristic facial features may include an abnormally large head (macrocephaly); low-set ears with large, thick lobes; unusually thick lips; a large, depressed nasal bridge; abnormally wide nostrils (nares); and a coarse facial appearance. In addition, affected children may have unusually curly hair and/or sparse, thin hair on the front (anterior) of the head. Some children have folds of skin over the inner corners of the eyes (epicanthal folds).

In early childhood relative overgrowth of the hindbrain compared to the space available in the posterior fossa of skull cavity can result in crowding and neurologic problems. Because severe crowding requires surgical intervention, screening with brain and cervical spine MRI has been suggested.

Eye and vision changes are common and include nystagmus (rapid eye movements) in younger individuals, strabismus and rarely in older individuals keratoconus (abnormal thickening of the cornea).

Children with Costello syndrome often have certain heart abnormalities. These may include structural malformations of the heart that are present at birth (congenital heart defects); abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy); leakage of the valve between the left upper (atrial) and lower (ventricular) heart chambers (mitral valve prolapse); and/or other cardiac defects. Associated symptoms and findings may include abnormal heart sounds (heart murmurs) that may be detected by a physician through use of a stethoscope; shortness of breath, particularly upon exertion; faintness; chest pain; abnormal heart rhythms (arrhythmias); and/or other findings that may potentially lead to life-threatening complications without appropriate treatment.

Affected individuals have an approximately 15% lifetime risk to develop malignant tumors such as a cancer of the muscle tissue (rhabdomyosarcoma), a cancer of the nerve cells (neuroblastoma), and transitional cell carcinoma of the bladder.

In some cases, the symptoms and findings of Costello syndrome overlap with two similar disorders known as Noonan syndrome and cardiofaciocutaneous syndrome which are caused by mutations in different genes.

Question 32

Costello syndrome causes

Answer 32

Costello syndrome is inherited as an autosomal dominant genetic condition and is caused my mutations in the HRAS gene. Mutations in this gene result in production of an abnormal H-Ras protein that leads to continuous cell growth and division.

Question 33

Kallman syndrome

Answer 33

Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.

This disorder is a form of hypogonadotropic hypogonadism, which is a condition resulting from a lack of production of certain hormones that direct sexual development. These hormones are normally made in a part of the brain called the hypothalamus. Males born with hypogonadotropic hypogonadism often have an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males, the start of monthly periods (menstruation) and breast development in females, and a growth spurt in both sexes. Without treatment, most affected men and women are unable to have biological children (infertile).

In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell. Many people with Kallmann syndrome are not aware that they are unable to detect odors until the impairment is discovered through testing.

Kallmann syndrome can have a wide variety of additional signs and symptoms. These include a failure of one kidney to develop (unilateral renal agenesis), abnormalities of bones in the fingers or toes, a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a feature called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.

Question 34

McCune - Albright syndrome

Answer 34

McCune-Albright syndrome is a disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues.

People with McCune-Albright syndrome develop areas of abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasia. Polyostotic means the abnormal areas (lesions) may occur in many bones; often they are confined to one side of the body. Replacement of bone with fibrous tissue may lead to fractures, uneven growth, and deformity. When lesions occur in the bones of the skull and jaw it can result in uneven (asymmetric) growth of the face. Asymmetry may also occur in the long bones; uneven growth of leg bones may cause limping. Abnormal curvature of the spine (scoliosis) may also occur. Bone lesions may become cancerous, but this happens in fewer than 1 percent of people with McCune-Albright syndrome.

In addition to bone abnormalities, affected individuals usually have light brown patches of skin called café-au-lait spots, which may be present from birth. The irregular borders of the café-au-lait spots in McCune-Albright syndrome are often compared to a map of the coast of Maine. By contrast, café-au-lait spots in other disorders have smooth borders, which are compared to the coast of California. Like the bone lesions, the café-au-lait spots in McCune-Albright syndrome may appear on only one side of the body.

Girls with McCune-Albright syndrome may reach puberty early. These girls often have menstrual bleeding by age 2. This early onset of menstruation is believed to be caused by excess estrogen, a female sex hormone, produced by cysts that develop in one of the ovaries. Less commonly, boys with McCune-Albright syndrome may also experience early puberty.

Other endocrine problems may also occur in people with McCune-Albright syndrome. The thyroid gland, a butterfly-shaped organ at the base of the neck, may become enlarged (a condition called a goiter) or develop masses called nodules. About 50 percent of affected individuals produce excessive amounts of thyroid hormone (hyperthyroidism), resulting in a fast heart rate, high blood pressure, weight loss, tremors, sweating, and other symptoms. The pituitary gland (a structure at the base of the brain that makes several hormones) may produce too much growth hormone. Excess growth hormone can result in acromegaly, a condition characterized by large hands and feet, arthritis, and distinctive facial features that are often described as “coarse.” Excess growth hormone secretion may also lead to increased expansion of the fibrous dysplasia in the bones, most visibly in the skull. Rarely, affected individuals develop Cushing syndrome, an excess of the hormone cortisol produced by the adrenal glands, which are small glands located on top of each kidney. Cushing syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems. In people with McCune-Albright syndrome, Cushing syndrome occurs only before age 2.

Problems in other organs and systems, such as noncancerous (benign) gastrointestinal growths called polyps and other abnormalities, can also occur in McCune-Albright syndrome.

Question 35

Cri-du-chat syndrome

Answer 35

Cri-du-chat (cat’s cry) syndrome, also known as 5p- (5p minus) syndrome, is a chromosomal condition that results when a piece of chromosome 5 is missing. Infants with this condition often have a high-pitched cry that sounds like that of a cat. The disorder is characterized by intellectual disability and delayed development, small head size (microcephaly), low birth weight, and weak muscle tone (hypotonia) in infancy. Affected individuals also have distinctive facial features, including widely set eyes (hypertelorism), low-set ears, a small jaw, and a rounded face. Some children with cri-du-chat syndrome are born with a heart defect.

Question 36

Wilsons disease presentation

Answer 36

Fatigue, lack of appetite or abdominal pain
A yellowing of the skin and the whites of the eye (jaundice)
Golden-brown eye discoloration (Kayser-Fleischer rings)
Fluid buildup in the legs or abdomen
Problems with speech, swallowing or physical coordination
Uncontrolled movements or muscle stiffness

Question 37

Wilsons disease cause

Answer 37

Wilson’s disease is inherited as an autosomal recessive trait
copper isn’t eliminated properly and instead accumulates, possibly to a life-threatening level.

Question 38

Wilsons disease complications

Answer 38

Scarring of the liver (cirrhosis). As liver cells try to make repairs to damage done by excess copper, scar tissue forms in the liver, making it more difficult for the liver to function.
Liver failure. This can occur suddenly (acute liver failure), or it can develop slowly over years. A liver transplant might be a treatment option.
Persistent neurological problems. Tremors, involuntary muscle movements, clumsy gait and speech difficulties usually improve with treatment for Wilson’s disease. However, some people have persistent neurological difficulty despite treatment.
Kidney problems. Wilson’s disease can damage the kidneys, leading to problems such as kidney stones and an abnormal number of amino acids excreted in the urine.
Psychological problems. These might include personality changes, depression, irritability, bipolar disorder or psychosis.
Blood problems. These might include destruction of red blood cells (hemolysis) leading to anemia and jaundice.

Question 39

Wilson’s disease treatment

Answer 39

Penicillamine (Cuprimine, Depen). A chelating agent, penicillamine can cause serious side effects, including skin and kidney problems, bone marrow suppression, and worsening of neurological symptoms. Penicillamine should be used cautiously if you have a penicillin allergy. It also keeps vitamin B-6 (pyridoxine) from working, so you'll need to take a supplement in small doses.
Trientine (Syprine). Trientine works much like penicillamine but tends to cause fewer side effects. Still, neurological symptoms can worsen when taking trientine.
Zinc acetate (Galzin). This medication prevents your body from absorbing copper from the food you eat. It is typically used as maintenance therapy to prevent copper from building up again after treatment with penicillamine or trientine.

Zinc acetate might be used as primary therapy if you can’t take penicillamine or trientine. Zinc acetate can cause stomach upset.