Apert Syndrome : A genetic disorder

Apert Syndrome


Introduction

Apert syndrome is a rare genetic disorder that is characterized by specific craniofacial and limb abnormalities. It is caused by a genetic mutation in the FGFR2 gene on chromosome 10. The mutation can be inherited from a parent who has Apert syndrome or it can be a spontaneous (new) mutation. Studies show that Apert syndrome tends to occur more often in children with older fathers. Furthermore, all new mutations (those that have not been inherited by an affected parent) have been shown to occur exclusively in the FGFR2 gene received by the father. Apert syndrome occurs in 1 out of 100,000 to 160,000 live births and affects males and females equally. The first reported case of the syndrome was in 1848 by S.W. Wheaton, and in 1906, a French physician named E. Apert described nine cases and defined the syndrome.

Features and Characteristics

The following characteristics have been found in children with Apert syndrome:

• Prematurely fused cranial sutures
• Retruded (or sunken) mid-face
• Fused fingers
• Fused toes
• Brachycephaly (short wide head)
• Acrocephaly (high prominent forehead)
• Flattened back of skull
• Prominent eyes - may be spaced widely apart or slant downward
• Strabismus
• Prominent mandible
• Depressed nasal bridge and small anteverted nose
• Down-turned corners of the mouth
• Low set ears (as well as hearing loss)
• Cleft palate
• Severe acne in teens
• Hydrocephalus
• Dental abnormalities (malposition of the teeth, crowding of the teeth, delayed tooth eruption, high-arched narrow palate, thickened ridges that support the teeth)
• Internal organ abnormalities including heart defects and abnormalities of the trachea,
  
• uterus, and brain

Skin manifestations of Apert syndrome

Hyperhidrosis Synonychia Brittle nails Severe acne in puberty Interruption of the eyebrows Hypopigmentation Hyperkeratosis Paronychial infections of plantar skin Excessive skin wrinkling of forehead Dimples at knuckles, shoulders and elbows

Prematurely Fused Cranial Sutures

Retruded Mid-face

Fused Fingers and Toes

Diagnosis

The diagnosis can be made by a skull x-ray, which will confirm premature closure of the skull, and by a clinical exam. The combination of the craniofacial problems and the fused fingers and toes is what distinguishes Apert syndrome from other similar syndromes. Since the defect which causes Apert syndrome has been identified, genetic testing can be provided to confirm a diagnosis.

Treatment

Treating a child with Apert syndrome is best accomplished with a team approach. This would include a craniofacial surgeon, neurosurgeon, ENT specialist, audiologist, speech pathologist, oral surgeon, psychologist, ophthalmologist, and an orthodontist. The majority of treatment methods is surgical and the individual will likely require many operations. Aside from the surgeries required to correct the craniofacial problems and the fused fingers and toes, there may be other potential surgeries to improve the upper airway, address severe eye problems, or correct dental issues.

Prader Willi Syndrome: A short Review

Prader-Willi syndrome (Summarized By Me)

simplified

Prader-Willi syndrome (abbreviated PWS) is a very rare genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome.

Diagnosis/testing
genetic testing, specifically DNA-based methylation testing to detect the absence of the paternally contributed Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on chromosome 15q11-q13. Such testing detects over 97% of patients. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings.

PWS phenotype
Clinical Features

In Utero:
Reduced fetal movement
Frequent abnormal fetal position
At Birth:
Often breech or caesarean births
Lethargy
Hypotonia
Feeding difficulties (due to poor muscle tone affecting sucking reflex)
Difficulties establishing respiration
Hypogonadism
Infancy:
Failure to thrive (continued feeding difficulties)
Delayed milestones/intellectual delay
Excessive sleeping
Strabismus
Scoliosis (often not detected at birth)
Childhood:
Speech delay
Poor physical coordination
Hyperphagia (over-eating) from age 2 - 4 years. Note change from feeding difficulties in infancy
Excessive weight gain
Adolescence:
Delayed puberty
Short stature
Obesity
Extremely flexible
Adulthood:
Infertility (males and females)
Hypogonadism
Sparse pubic hair
Obesity
Hypotonia
Learning disabilities/borderline intellectual functioning (but some cases of average intelligence)
Proneness to diabetes mellitus
Extremely flexible
General physical appearance (adults)
Prominent nasal bridge
Small hands and feet
Soft skin, which is easily bruised
Excess fat, especially in the central portion of the body
High, narrow forehead
Almond shaped eyes with thin, down-turned lips
Light skin and hair relative to other family members
Lack of complete sexual development
Always picking at their skin
Stria
Delayed motor development

Neuro-cognitive
Individuals with PWS are at risk of learning and attention difficulties. Curfs and Frym (1992) conducted research into the varying degrees of learning disability found in Prader Willi Syndrome (PWS).[5] Their results were as follows:
5%...IQ above 85 (Average to low average intelligence)
27%..IQ 70 - 85 (Borderline intellectual functioning)
34%..IQ 50 - 70 (Mild intellectual disability)
27%..IQ 35 - 50 (Moderate intellectual disability)
5%...IQ 20 - 35 (Severe intellectual disability)
<1%..iq>

Behavioral
Prader-Willi syndrome is also frequently associated with an extreme and insatiable appetite, often resulting in morbid obesity. There is currently no consensus as to the cause for this particular symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamus.[6] Given that the hypothalamus regulates many basic processes, including appetite, there may well be a link. However, no organic defect of the hypothalamus has been discovered on post mortem investigation.[6]

Endocrine
There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat free mass (FFM), have reduced LBM and total energy expenditure, and have decreased bone density.
PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature adrenarche in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy.

Treatment
Prader-Willi syndrome has no cure. However, several treatments are in place to lessen the condition's symptoms. Growth hormone replacement therapy improves body composition and increases linear height. During infancy, subjects should undergo therapies to improve muscle tone. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment as well as extra help. Throughout their lives, the subject's food should literally be kept under lock and key, since the largest problem associated with the syndrome is severe obesity.
Because of severe obesity, obstructive sleep apnea is a common sequela, and a CPAP (continuous positive airway pressure) machine is often needed.

Marfan Syndome: Tall is not always Gold

Marfan syndrome

is an autosomal dominant genetic disorder of the connective tissue characterized by disproportionately long limbs, long thin fingers, a typically tall stature, and a predisposition to cardiovascular abnormalities, specifically those affecting the heart valves and aorta. The disorder may also affect numerous other structures and organs — including the lungs, eyes, dural sac surrounding the spinal cord, and hard palate. It is named after Antoine Marfan, the French pediatrician

Symptoms

Three systems are predominantly affected.

Ocular:
upward lens dislocation
retinal detachment

Skeletal:
arachnodactyly
tall with disproportionately long legs and arms - the span of the arms is greater than the height
pectus excavatum
spinal abnormalities - spondylolisthesis, scoliosis
increased incidence of slipped upper femoral epiphysis
generalised joint laxity with predisposition to flat feet or dislocation of patella or shoulder

Cardiovascular
- affecting the aortic and mitral valves and the ascending aorta:
dilatation of the aorta may be noted at any age, beginning at the aortic valve and usually confined to the ascending aorta
aortic insufficiency may result from stretching of the aortic valve ring and a dissecting aneurysm of the aorta may be a terminal event. Rarely, it occurs during pregnancy
mitral insufficiency results from redundant cusps and chordae tendineae
other cardiac malformations have occasionally been reported
Mental development is normal.

The average lifespan of an affected individual is 40 to 50 years.



Skeletal system
The most readily visible signs are associated with the skeletal system. Many individuals with Marfan Syndrome grow to above average height. Some have long slender limbs with fingers and toes that are also abnormally long and slender (arachnodactyly). This long, slender body habitus and long, slender limbs are known as dolichostenomelia. An individual's arms may be disproportionately long, with thin, weak wrists. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal signs. Abnormal curvature of the spine (scoliosis) is common, as is abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, stooped shoulders, unexplained stretch marks on the skin and thin wrists. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws.


Eyes
Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness and astigmatism are common, but farsightedness can also result. Periodic eye exams can lead to an ophthalmologist or optometrist discovering dislocation, or subluxation, of the crystalline lens in one or both eyes (ectopia lentis) by carefully observing these structures using a slit-lamp biomicroscope. This can be differentiated from the similar condition homocystinuria, where the dislocation is inferonasal; in Marfan's the dislocation is superotemporal. Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina.Early onset glaucoma can be another complication.


Cardiovascular system
The most serious conditions associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or pain in the left chest, back, shoulder, or arm, can bring a person into the doctor's office. Cold arms, hands and feet can also be seriously linked to marfan syndrome because of a loss of blood circulation. A heart murmur heard on a stethoscope, an abnormal reading on an electrocardiogram, or symptoms of angina can lead a doctor to order an echocardiogram. This can reveal signs of leakage or prolapse of the mitral or aortic valves that control the flow of blood through the heart. (See mitral valve prolapse.) However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue in the ascending aorta causes an aortic aneurysm or even aortic dissection.



Lungs
Marfan syndrome is a risk factor for spontaneous pneumothorax. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, death. Marfan syndrome has also been associated with sleep apnea and idiopathic obstructive lung disease.


Central nervous system
Another condition that can reduce the quality of life for an individual, though not life-threatening, is dural ectasia, the weakening of the connective tissue of the dural sac, the membrane that encases the spinal cord. Dural ectasia can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches. Such symptoms usually diminish when the individual lies flat on his or her back. These types of symptoms might lead a doctor to order an X-ray of the lower spine. Dural ectasia is usually not visible on an X-ray in the early phases. A worsening of symptoms and the lack of finding any other cause should eventually lead a doctor to order an upright MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in an upright MRI image as a dilated pouch that is wearing away at the lumbar vertebrae. Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts.