Lung Function Tests

http://www.webmd.com/lung/lung-function-tests

http://www.webmd.com/lung/bronchoscopy-16978

http://www.advanceweb.com/web/AstraZeneca/focus_on_asthma_copd_issue5_Bronchodilator/issue5.html

http://www.lung.org/lung-disease/bronchiectasis/

http://www.webmd.com/asthma/guide/peak-flow-meter

http://www.webmd.com/a-to-z-guides/blood-culture

http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm

Osmolarity vs. Osmolality and Osmotic Gap

OSMOLARITY

Osmolarity:
- is an estimation of the osmolar concentration of plasma
- is proportional to the number of particles per litre of solution
- is a calculated value (from a formula or an equation)
- is derived from the values determined for Na+, K+, urea and glucose concentrations
- is expressed as mmol/L
- is unreliable in various conditions:
   - hyperlipidaemia in nephrotic syndrome (pseudohyponatraemia)
   - hyperproteinaemia

Calculation of osmolarity:

The following equations can be used to calculate osmolarity:

Equation 1:

Calculated osmolarity = 2 (Na+) + 2 (K+) + Glucose + Urea (all in mmol/L)

The doubling of sodium accounts for chloride, its main associated anion.
The exclusion of potassium is because K+ values are too small compared to sodium.

Equation 2:

Calculated osmolarity = 2 (Na+) + Glucose + Urea (all in mmol/L)

The doubling of sodium accounts for the negative ions associated with sodium (mainly chloride).
The exclusion of potassium is because the values are too small compared to sodium.

Normal values for osmolarity:

??


OSMOLALITY

Osmolality:
- is an estimation of the osmolar concentration of plasma
- is proportional to the number of particles per kilogram of solvent
- is expressed as mOsmol/kg (the SI unit is mmol/kg but mOsmol/kg is still widely used).
- is measured by clinical laboratories using an osmometer. There are 2 types:
  - a freezing-point depression osmometer
  - a vapour-pressure depression osmometer

Normal values for osmolality:

Normal osmolality of extracellular fluid (ECF) is 280-295 mOsmol/kg.

Uses of osmolality:
- it provides a snapshot of the number of solutes present in the blood (serum), urine, or stool
- it is ordered to help evaluate the body's water balance
- it is ordered to find out its ability to produce and concentrate urine
- it is used to help investigate low sodium levels (hyponatremia)
- it is used to detect the presence of toxins such as methanol and ethylene glycol (see osmotic particles)
- it is used to monitor osmotically active drug therapies such as mannitol, used to treat cerebral edema.
- it is also ordered to help monitor the effectiveness of treatment for any conditions found to be affecting a person's osmolality.


OSMOTIC PARTICLES

Osmotic particles attract or "pull" water:

1. Sodium, glucose, and urea account for the majority of the osmotically active particles in the blood.
2. Extraneous osmotically active substances are ethanol, ethylene glycol, mannitol, methanol, or other toxins.

OSMOTIC GAP

Osmotic gap:
- is also called osmolal gap
- is an arbitrary measure of the difference between the actual osmolality (measured by the laboratory) and the calculated osmolarity

Normal values for osmotic gap:

Osmotic gap is normally less than 10-15 mOsmol/kg (refer local laboratory for range).

Increased values for osmotic gap:

Where the osmotic gap is increased, it indicates the presence of other osmotically active solutes which are not taken into account in the calculated osmolality - eg, in methanol or ethylene glycol ingestion. Victims commit suicide by drinking methanol. Ethylene glycol is radiator fluid for cars. Victims accidentally drink ethylene glycol.

Typical causes of an increased osmolar gap:

acetone, decreased serum water, ethanol, ethylene glycol, glycerol, hyperlipidemia, hyperproteinemia, isopropyl alcohol,laboratory error, sorbitol


OSMOMETER

So far we have used the Gonotec Osmomat 3000 osmometer (freezing-point depression). It requires a small amount of sample (50 microlitres). There are tubes for smaller volumes (15 microlitres).

http://www.gonotec.com/products/osmomat-3000

External links:
http://www.patient.co.uk/doctor/osmolality-osmolarity-and-fluid-homeostasis
http://labtestsonline.org/understanding/analytes/osmolality/tab/test
http://www.rnceus.com/renal/renalosmo.html
http://www.globalrph.com/anion_gap_review.htm
http://www.wolflabs.co.uk/laboratory-products/osmometers/osmomat-3000/10092120
http://pdfs.wolflabs.co.uk/service/Gonotec_Osmometer_3000_manual.pdf
http://camblab.info/wp/wp-content/uploads/2014/03/mod_200plus.gif

Pituitary Gland

Biochemistry

THEORY

FUNCTIONS OF PITUITARY HORMONES

Hormones secreted from the pituitary gland help control the following body processes:
1. Growth
2. Blood pressure
3. Some aspects of pregnancy and childbirth including stimulation of uterine contractions during childbirth
4. Breast milk production
5. Sex organ functions in both males and females
6. Thyroid gland function
7. The conversion of food into energy (metabolism)
8. Water and osmolarity regulation in the body
9. Water balance via the control of reabsorption of water by the kidneys
10. Temperature regulation
11. Pain relief

DISEASES INVOLVING THE PITUITARY GLAND

Some of the diseases involving the pituitary gland are:
1. Central diabetes insipidus caused by a deficiency of vasopressin.
2. Gigantism and acromegaly caused by an excess of growth hormone. --- PBL Ph2 Yr2 MD Wk1 Topic1
3. Hypothyroidism caused by a deficiency of thyroid-stimulating hormone.
4. Hyperpituitarism, the increased (hyper) secretion of one or more of the hormones normally produced by the pituitary gland.
5. Hypopituitarism, the decreased (hypo) secretion of one or more of the hormones normally produced by the pituitary gland.
6. Panhypopituitarism a decreased secretion of most of the pituitary hormones.
7. Pituitary tumours.
8. Pituitary adenomas, noncancerous tumors that occur in the pituitary gland.

GROWTH HORMONE (GH)

GH is growth hormone, or somatotropin
GH is a single polypeptide chain containing 191 amino acids.
GH has structural similarity with prolactin and human placental lactogen.
GH is synthesised by acidophils (somatotropic cells) of anterior pituitary.
GH has a circadian rhythm;
- plasma concentration of GH is less than 2 ng/ml during day time,
- with secretory peak appearing 3 hr after meals.
- maximum level of GH is seen during deep sleep;
- this peak is required for anabolic and repair process.

GH secretion is regulated by the balance between GHRH and GHIH (somatostatin).
The regulation of secretion is predominantly inhibitory.
Hypoglycemia stimulates GH secretion.
Hyperglycemia suppresses GH secretion.

The metabolic effect of GH is partly mediated by somatomedin.
Somatomedin is also known as insulin-like growth factor-1 (IGF-1).
The growth of long bones is stimulated by IGF-1.
IGF-1 level is almost always raised in acromegaly.
A single plasma level of IGF-1 reflects mean 24-hour GH level and is useful in diagnosis.

GH increases the uptake of amino acids by cells.
GH enhances protein synthesis, and produces positive nitrogen balance.
The anti-insulin effect of GH causes lipolysis and hyperglycemia.
The overall effect of GH is to stimulate growth of soft tissues, cartilage and bone.
GH is anabolic.

Excess secretion by GH secreting tumour, leads to
- gigantism in children
- acromegaly in adults.

Deficiency of GH secretion in early childhood results in pituitary dwarfism.
Dwarfism may also result from congenital deficiency of GH due to end organ resistance.
Dwarfism is treated by giving GH produced by recombinant technology.

--------------

PRACTICAL

SERUM GH

The samples are collected during sleep and also during waking hours to assess the circadian rhythm.

Random plasma GH is elevated.

GH SUPPRESSION TEST (glucose suppression test)

Basis of the GH suppression test:
Dynamic tests like stimulation of secretion by insulin induced hypoglycemia and inhibition by hyperglycemia are undertaken to arrive at a diagnosis.

Procedure:
Measure plasma glucose and GH during a standard OGTT.

Interpretation:
(i) In normal person:
Normally in healthy individuals, oral administration of 100 g glucose causes a reduction of the GH level to <5 br="" ml.="" ng=""> (ii) In acromegaly:
Acromegalics (with GH excess) fail to suppress GH level. In acromegaly, the GH levels may decrease, increase or show no change. However, they do not decrease to less than 5 ng/ml and this lack of response establishes the diagnosis. High GH levels are sustained in acromegalics.

(iii) Patient:
In this patient, the GH level is not suppressed (ie sustained) and remained high during the test, Therefore, patient suffers from acromegaly.

BLOOD GLUCOSE

Check if patient is diabetic.
Check for hyperglycaemia.

RBS is high (>11.1 mmol/L) - patient has hyperglycaemia most likely due to diabetes mellitus as patient is symptomatic with lethargy, polyuria and polydipsia.

OGTT

Oral glucose tolerance test (OGTT). Administer 100 g glucose solution (dissolve in a glass of water).

HBA1C

Glycosylated haemoglobin (HbA1c) provides an index of the average blood glucose concentration over the last 6 weeks (lifespan of Hb molecules).

URINALYSIS (urine dipstick test)

Test urine for sugar, ketones and protein.
Urine sugar - check for glycosuria (in polyuria and polydipsia)
Urine ketone - check for ketonuria which occurs in diabetic ketonuria
Urine protein - check for proteinuria (renal involvement in diabetes)

Urine sugar is positive - glycosuria is not diagnostic of diabetes but indicates the need for further investigation.

Urine protein is negative - indicates there is no renal involvement as diabetic nephropathy.

Urine ketone is negative - indicates patient does not have ketoacidosis.

UREA, CREATININE and ELECTROLYTES (renal profile)

Serum urea, creatinine and electrolytes - to check for renal status as patient has polyuria.

Serum sodium and potassium are normal - indicate that patient does not have hypoadrenalism, hypothyroidism (hyponatraemia), or diabetes insipidus (hypernatraemia).

Serum urea - decreased serum urea in acromegaly.

Serum creatinine - increased serum creatitine in gigantism and acromegaly.

CALCIUM

Serum calcium - high with hypercalciuria in acromegaly. Matches with renal stone formation.

Hypercalciuria and hyperphosphaturia are observed in acromegalic patients. It is well known that acromegaly is associated with the disturbances of Ca and PO4 metabolism, and consequently with an increased risk of Ca stones.

ENZYMES

Heart muscle enzyme:
Creatinine kinase (CK) - elevated in myopathy

----------

Abnormal findings

ENT / ORL-HNS:
Coarse facies - Increased level of GH causes thickening of the soft tissues, overgrowth of the malar, frontal and facial bones combined with prognathism to produce the coarse facial features called acromegalic facies.
Facial and infraorbital puffiness - ?
Broad nose
Big ear

Dentistry:
Widening of the teeth / interdental separation
Prognathism - widely spaced teeth

Speech Pathology:
Large tongue
Thick lips
Deep voice

Medicine:
Hypertension - investigate further
CXR
ECG
Echocardiogram
Urinalysis
Fasting blood for lipids and glucose
Serum urea, creatinine and electrolytes

Cardiology:
Heart failure
Proximal myopathy

Ophthalmology:
Visual field examination
Visual field testing by Goldmann perimetry - it can assess any visual field defect as upper temporal quarantonopias and bitemporal hemianopias. Perimetry can also assess the tujour size.
Papilloedema - increased intracranial pressure from the pituitary tumour causes edema of the optic disc.

-------

Endocrinology

Pituitary
- anatomy of the pituitary gland
- hormones released by the anterior lobe of pituitary: GH, ACTH, LH, FSH, TSH, aMSH (intermediate lobe), PRL, bLPH
- hormones released by the posterior lobe of pituitary: ADH, oxytocin
- processes involved in the release of these hormones
- biological functions of these hormones
- control mechanisms that affect hormone production, release and function
- types of pituitary tumours
- hyperfunction, hypofunction

Assessment of anterior pituitary reserve or function - as patient may have hypopituitarism:
Basal LH
FSH
Testosterone
ACTH
Cortisol
Free/Total T4
TSH

Triple Stimulation Test
LHRH/GnRH, TRH, insulin tolerance test (ITT) can be done to assess the function of the anterior pituitary. Early LH failure can occur

followed by hypothyroidism and hypoadrenalism.

Hypothyroidism (free/total T4 is low with a low or normal TSH level) must be excluded since this is a cause of hyperprolactinaemia.

Serum prolactin
Mild to moderate hyperprolactinaemia occurs in pituitary tumour.
Pituitary tumour is suspected if patient has papilloedema, indicating increased intracranial pressure from a pituitary tumour.

Serum prolactin - is due to hyperprolactinaemia that can result from a pituitary tumour, which is evident from the CT scan of the brain.

Endocrinology/Medicine:
Galactorrhoea
Edema plus other signs of hypopituitarism
Goitre

-----

Patient workup:

History
Physical examination
Presenting clinical features
Pathological features
Radiological features
Laboratory investigations
Deduce possible patient problem

-----

Medicine

Pathophysiology of:
I. Pituitary hypersecretion:
   - Gigantism
   - Acromegaly - face, hands **
   - Prolactin-induced infertility
   - Craniopharyngioma
   - Cushing's disease
II. Pituitary hyposecretion:
   - Pituitary dwarfism
   - Panhypopituitarism
   - Diabetes insipidus

-----

Radiology

Imaging studies:

Skull X-ray - enlargement/widening of the pituitary fossa, double flooring, calcification

MRI scan of the pituitary - to rule out suspicion of a pituitary tumour as patient has history of headache and papilloedema.

Lateral X-ray of the heel - assessment of soft tissue thickness by measuring heel pad thickness.

X-ray of hand - Large hands, thickened and bulky with blunt spade-like fingers (similar findings in the toes - spade-like feet)
Large hands and sweaty - The hands enlarge from increased soft tissue growth. Sebaceous activity increases causing excessive sweating.
Increased joint space due to hypertrophy of cartilage, cortical thickening with result in squared appearance of the metacarpals.
Small exostoses in the areas of tendons and ligament insertion and are obvious in the head of the metacarpals.
Tufting of the terminal phalanges producing an "arrow-head" appearance.

------
Possible complications:

Cardiovascular problems - CAD, related to HPT and DM
Arthritis - occurs prematurely in spine and weght-bearing joints (hips, knees)
Malignancy - colon cancer is increased.

Arthropathy - disease of the joints
Tight rings - excessive fat

------

Treatment and Management

Surgery - vi transphenoid/transfrontal route

Radiotherapy

Medical therapy - using a somatostatin analogue (octreotide) or dopamine agonist (bromocriptine).

Principles of hormone replacement therapy (HRT) in pituitary dysfunction

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Further Reading

Basic and Clinical Endocrinology. Francis S. Greenspan. Acromegaly and gigantism. Clinical findings on page 119.

Steven WJ Lamberts. Non-functioning pituitary tumours and hypopituitarism. Medicine International on Endocrine Diseases. No. 38

Volume 11, 1997, pages 1-4.

JAH Wass. Acromegaly. Medicine International on Endocrine Diseases. No 38 Volume 11, 1997, pages 5-6.
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Videos

http://umm.edu/health/medical/ency/animations/pituitary-gland

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Research & Case Studies

http://www.eje-online.org/content/162/6/1035.full


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Websites

http://www.chronolab.com/point-of-care/index.php?option=com_content&view=article&id=388&Itemid=63

http://www.rnceus.com/renal/renalcreat.html

Lactase deficiency

Synonyms
Lactose intolerance
Lactase deficiency
Hypolactasia

Terminologies
Lactose: a disaccharide made up of galactose and glucose
Lactase: an enzyme that splits lactose

Cause
Patients lack the enzyme lactase (lactase deficiency) and therefore cannot digest lactose, a milk sugar, which is also found in processed dairy foods. They cannot tolerate milk and dairy products (lactose intolerance) and suffer from diarrhoea if they take such foods.

What is lactose?
Lactose is a water-soluble compound. Lactose is a sugar found in milk. Chemically and structurally, lactose is a disaccharide, meaning it is a compound made up of 2 simple sugars - glucose and galactose. Lactose can be split by the enzyme lactase to give the 2 simple sugars (called monosaccharides).

Enzyme action
The enzyme lactase is found in the duodenum (first part of the small intestines). Lactase breaks down lactose to glucose and galactose.

Symptoms
Consumption of foods containing significant amounts of lactose (minus added lactase) causes symptoms which may include:

1. abdominal bloating and
2. cramps, 
3. flatulence, 
4. diarrhea, 
5. nausea, 
6. borborygmi (rumbling stomach), or 
7. vomiting.

Precautions

1. As a genetic disorder, lactose intolerance prevents babies from drinking human breast milk, which nearly quarters its risk of Sudden Infant Death Syndrome.
2. Some studies have produced evidence that milk consumption by lactose intolerant individuals may be a significant cause of inflammatory bowel disease.

Types of lactase deficiency

There are 3 types of lactase deficiency:

1. Primary (genetic; only affects adults) - most common
2. Secondary (acquired or develops due to damage of duodenum) - transient
3. Congenital (present at birth; rare; autosomal recessive; affects babies) - babies cannot consume breast milk

Lactase levels
Lactase levels vary widely depending on age, population and food consumption.

1. Lactase levels decrease after weaning from milk, and children become lactose intolerant after weaning.
2. Lactase levels persist into adulthood if children are not weaned from dairy products.
3. 75% adults have decreased lactase levels.
4. 5% adults in northern Europe have decreased lactase levels (they could reflect resident migrants).
5. 71% adults of Sicily have reduced lactase levels (Sicily is a Mediterranean country).
6. 90% adult Africans and Asians have lactase deficiency (a small 10% can tolerate milk - they could be resident Caucasians).
7. Lactase persistence could be due to genetic mutation.

Dairy foods that contain lactose:

1. milk (full-cream and skimmed)
2. yoghurt (fresh and frozen)
3. cheese (soft and hard)
4. butter

Non dairy foods containing lactose 

Label reading is essential, as commercial terminology varies according to language and region. Lactose is present in two large food categories—conventional dairy products, and as a food additive (casein, caseinate, whey), which may contain traces of lactose. Food additives are used for adjusting the texture, flavour and adhesive qualities of processed food. Milk and milk products are often added to processed foods—foods that have been altered to prolong their shelf life. People with lactose intolerance should be aware of the many food products that may contain even small amounts of lactose.

1. lactoserum,
2. casein,
3. caseinate, 
4. whey, 
5. milk solids, 
6. modified milk ingredients  
7. meats (sausages/hot dogs, sliced meats, pâtés), 
8. gravy stock powder, 
9. margarines,
10. sliced breads,
11. breakfast cereals, 
12. potato chips, 
13. medications, 
14. pre-prepared meals, 
15. meal replacement (powders and bars), 
16. protein supplements (powders and bars)  
17. barbecue sauces and 
18. liquid cheeses used in fast-food restaurants
19. bread and other baked goods
20. waffles, 
21. pancakes, 
22. biscuits, cookies, and mixes
23. processed breakfast foods (doughnuts, frozen waffles and pancakes, toaster pastries, and sweet rolls)
24. processed breakfast cereals
25. instant potatoes, 
26. soups, and 
27. breakfast drinks
28. potato chips, 
29. corn chips, and other processed snacks
30. processed meats (beef, sausage, hot dogs, and lunch meats),
31. salad dressings
32. liquid and powdered milk-based meal replacements
33. candies
34. non-dairy liquid and powdered coffee creamers (made from palm oil)
35. non-dairy whipped toppings

Diagnosis

The patient is challenged with food containing high lactose, and is monitored for 30 minutes to 2 hours for clinical symptoms of lactose intolerance.

Confirmatory tests

After lactose intolerance is diagnosed, confirmatory tests are done. There 6 ways to confirm lactose intolerance. The choice of tests selected are based on the patient's age (infant, adult) and condition (pregnancy) and clinical laboratory facilities available.

1. Hydrogen breath test - Elevated hydrogen levels indicate lactose intolerance.
2. Blood glucose test - needs overnight fasting. Take 1st blood sample and administer 50g lactose (solution). Blood is then drawn again at 30 minute, 1-hour, 2-hours, and 3-hours. If the lactose cannot be digested, blood glucose levels will rise by less than 20 mg/dL.
3. Stool acidity test - This test can be used to diagnose lactose intolerance in infants. The infant is given lactose to drink. If the infant is tolerant, the lactose is digested and absorbed in the small intestine; otherwise it is not digested and not absorbed and it reaches the colon. The bacteria in the colon, mixed with the lactose, cause acidity in stools. Stools passed after the ingestion of the lactose are tested for level of acidity. If the stools are acidic, the infant is intolerant to lactose. Stool pH in lactose intolerance is less than 5.5 (acidic stools).
4. Intestinal biopsy - This is done after a positive hydrogen breath test. A gastrointestinal endoscopy is done to confirm lactase deficiency. a) Modern techniques have enabled a bedside test to identify the presence of lactase enzyme on upper gastrointestinal endoscopy instruments. b) However, for research applications such as mRNA measurements, a specialist laboratory is required. The amount of mRNA present is determined by rPCR.
5. Stool sugar chromatography - details?
6. Genetic diagnosis - It is used in primary lactose intolerance. Lactase activity persistence in adults is associated with two polymorphisms: C/T 13910 and G/A 22018 located in MCM6 gene. These polymorphisms may be detected by molecular biology techniques, eg polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), using the DNA extracted from blood or saliva samples. Genetic kits specific for this diagnosis are available. The procedure consists of extracting and amplifying DNA from the samples, followed with a hybridisation protocol in a strip. Colored bands are obtained as final result. Depending on the different combination, it would be possible to determine whether the patient is lactose intolerant. This test allows a non-invasive definitive diagnosis.

Management

1. Pregnancy - About 44% of lactose-intolerant women regain the ability to digest lactose during pregnancy. This might be caused by slow intestinal transit and intestinal flora changes during pregnancy[citation needed].
2. Live yoghurt cultures - Lactose intolerance can also be managed by ingesting live yoghurt cultures containing Lactobacilli that are able to digest the lactose in other dairy products. This may explain why many South Asians though genetically lactose intolerant are able to consume large quantities of milk without much symptoms of lactose intolerance. Consuming live yoghurt cultures in lassi (a fermented milk drink) is common in the South Asian population. 
3. Avoiding lactose-containing products - Lactose intolerance is not an absolute condition. The reduction in lactase production, and the amount of lactose that can be tolerated varies from person to person. According to the U.S. National Institutes of Health (NIH), "Dietary control of lactose intolerance depends on people learning through trial and error how much lactose they can handle." Affected persons must learn to read and understand food labels.
4. Minimise occurence and symptoms - Since lactose intolerance poses no further threat to a person's health, the condition is managed by minimizing the occurrence and severity of symptoms. Berdanier and Hargrove recognise four general principles in dealing with lactose intolerance: (i) avoidance of dietary lactose, (ii) substitution to maintain nutrient intake, (iii) regulation of calcium intake and (iv) use of enzyme substitute.

External links:
http://en.wikipedia.org/wiki/Lactose_intolerance
http://digestive.niddk.nih.gov/ddiseases/pubs/lactoseintolerance/
http://www.ncbi.nlm.nih.gov/pubmed/17934640
http://www.ncbi.nlm.nih.gov/pubmed/16019716
http://www.ncbi.nlm.nih.gov/pubmed/17345962
http://www.ncbi.nlm.nih.gov/pubmed/19639477
http://www.ncbi.nlm.nih.gov/pubmed/15287817
http://www.ncbi.nlm.nih.gov/pubmed/17956597

What is a Normal Lactose Intolerance Test? KA Sikaris, AR McNeil, G Wilcox [Google this]

Adolf Kussmaul 1822-1902

Dr Kussmaul was a German doctor who studied medicine at the University of Heidelberg. Two things important which he put forth are: 1. Kussmaul's breathing, and 2. Kussmaul's sign.

They are noted in respiratory disorders, as occurs in acidosis when breathing is affected. In diabetic patients, the breathing is different - it is shallow and light, as if there is lack of air or oxygen deficiency. Thus, the term 'air hunger' is born.

In comatosed diabetic patients, also there is a difference in the breathing pattern.

More at:
Clin Med Res. Sep 2009; 7(3): 107–112.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757428/

Caudal Regression Syndrome (CRS)

Synonyms

Caudal regression syndrome
Sacral agenesis, congenital (agenesis of the lumbar spine, sacrum, and coccyx, and hypoplasia of the lower extremities)
Hypoplasia of the sacrum
Currarino syndrome
Caudal dysplasia
Caudal dysplasia sequence
Congenital sacral agenesis
Sacral regression
Lumbo sacral agenesis

Introduction

Caudal regression syndrome or sacral agenesis (or hypoplasia of the sacrum) is a congenital disorder in which there is abnormal fetal development of the lower spine—the caudal partition of the spine.

Incidence

It occurs at a rate of approximately one per 25,000 live births.

Signs

This condition exists in a variety of forms, ranging from partial absence of the tail bone regions of the spine to absence of the lower vertebrae, pelvis and parts of the thoracic and/or lumbar areas of the spine.

In some cases where only a small part of the spine is absent, there may be no outward sign of the condition.

In cases where more substantial areas of the spine are absent, there may be fused, webbed, or smaller lower extremities and paralysis (resembling the spread legs of a frog).

Bowel and bladder control is usually affected (affected children have to wear pampers even at school-going age).

Prognosis

There are four levels (or "types") of malformation.

1. The least severe indicates partial deformation (unilateral) of the sacrum.
2. The second level indicates a bilateral (uniform) deformation.
3. The most severe types involve a total absence of the sacrum.

1. Genitourinary system

Depending on the type of sacral agenesis, bowel or urinary bladder deficiencies may be present. A permanent colostomy may be necessary in the case of imperforate anus. Incontinence may also require some type of continence control system (e.g. self-catheterization) be utilized.

2. Musculoskeletal system

Occasionally if deformities of the knees, legs or feet would prove unresponsive to corrective action, amputation at the knee may be proposed.

Before more comprehensive medical treatment was available, full amputation of the legs at the hip was often performed.

More recently, the 'amputation' (actually a disarticulation because no cutting of the bone is involved) is done at the knee for those who have bent knee positions and webbing between thigh and calf to enable more ease of mobility and better seating.

Some children with knee disarticulation use prosthetic legs to walk.

Prosthetics for children without substantial hip and trunk control is usually abandoned in favor of faster and easier wheelchair mobility as the child's weight and age increases.

Children may 'walk' on their hands and generally are able to climb and move about to accomplish whatever they need and want to accomplish. (Walking on hands and dragging the bent legs is an adaptive feature in affected children. With strong hands, they can easily jump up onto a sturdy low table and sit on the table to do many things. When they are propped up on the table, they are the height of a seated child.)

Children more mildly affected may have normal gait and no need for assistive devices for walking.

Others may walk with bracing or crutches.

3. Brain development

There is typically no cognitive impairment associated with this disability. (The affected child has normal intelligence.)

Adults with this disability live independently, attend college, and have careers in various fields.

Etiology

There are many causes of this syndrome and the exact etiology is unknown.

1. Fetal development

The condition arises from some factor or set of factors present during approximately the 3rd week to 7th week of fetal development (first to second trimester).

Formation of the sacrum/lower back and corresponding nervous system is usually nearing completion by the 4th week of development (end of 1 month).

Due to abnormal gastrulation, the mesoderm migration is disturbed. This disturbance results in symptoms varying from minor lesions of the lower vertebrae to more severe symptoms such as complete fusion of the lower limbs.

2. Dietary deficiency

It has been speculated that the condition may be associated with certain dietary deficiencies including a lack or insufficient amounts of folic acid. Folic acid is required for nervous tissue development and that of the spinal cord.

3. Maternal diabetes

Sacral agenesis syndrome is a well-established congenital anomaly associated with maternal diabetes mellitus (not gestational diabetes). (Complications of maternal diabetes (retinopathy, nephropathy) is associated with caudal regression syndrome, and is detectable at 25 weeks gestation by x-ray of the foetus.)

The sacral agenesis syndrome is a severe congenital abnormality consisting of agenesis of the lumbar spine, sacrum, and coccyx, as well as hypoplasia of the lower extremities. It is considered the most characteristic of all congenital anomalies associated with maternal diabetes mellitus. We describe the sonographic and radiologic findings of agenesis of the lumbosacrococcygeal spine with lower limb and genital hypoplasia in the offspring of a woman with both diabetic retinopathy and nephropathy. The diagnosis was established at 25 weeks' gestation and was confirmed by radiologic evaluation of the neonate. Am J Obstet Gynecol. 1990 Mar;162(3):806-8.

However, other etiologic factors are presumably involved, as demonstrated by the rare incidence of caudal regression syndrome (1:60,000) compared to diabetes.

Certainly not all children born with Caudal Regression Syndrome have diabetic mothers.

4. Genetics and inheritance

The dominant inherited sacral agenesis is very often correlated with a mutation in the Hb9 (also called HlxB9) gene (shown by Sally Ann Lynch, 1995, Nature Genetics).

It may be the cause of sirenomelia ("Mermaid Syndrome") - the most severe form of caudal regression syndrome.


External links
Am J Obstet Gynecol. 1990 Mar;162(3):806-8.
Antenatal diagnosis of sacral agenesis syndrome in a pregnancy complicated by diabetes mellitus.
Sonek JD1, Gabbe SG, Landon MB, Stempel LE, Foley MR, Shubert-Moell K.

American Association of Neurological Surgeons (AANS)

Birth Defects Research for Children, Inc.
https://www.facebook.com/BDRCFL
YouTube: Because every birth defect has a cause

Tell Me a Story: Birth Defects Teaches Parents to Look at Life Differently

YouTube: Caudal Regression Syndrome

IEM: Lysosomal Storage Disease (LSD) - MPS II, Hunter Syndrome

Introduction

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and connective tissue.

Glycosaminoglycans (formerly called mucopolysaccharides) are also found in the synovial fluid that lubricates our joints.

People with a mucopolysaccharidosis disease either do not produce enough of one of the 11 enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these glycosaminoglycans collect in the cells, blood and connective tissues. The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning, and, in most cases, mental development.

The mucopolysaccharidoses are part of the lysosomal storage disease family, a group of more than 40 genetic disorders that result when a specific organelle in our bodies' cells – the lysosome – malfunctions.

The lysosome is commonly referred to as the cell’s recycling center because it processes unwanted material into substances that the cell can utilize.

Lysosomes break down unwanted matter via enzymes, highly specialized proteins essential for survival.

Lysosomal disorders like mucopolysaccharidosis are triggered when a particular enzyme exists in too small an amount or is missing altogether (enzyme deficiency).

Clinical features

The mucopolysaccharidoses share many clinical features but have varying degrees of severity.

These features may not be apparent at birth but progress as storage of glycosaminoglycans affects bone, skeletal structure, connective tissues, and organs.

Neurological complications may include damage to neurons (which send and receive signals throughout the body) as well as pain and impaired motor function. This results from compression of nerves or nerve roots in the spinal cord or in the peripheral nervous system, the part of the nervous system that connects the brain and spinal cord to sensory organs such as the eyes and to other organs, muscles, and tissues throughout the body.

Depending on the mucopolysaccharidosis subtype, affected individuals may have normal intellect or have cognitive impairments, may experience developmental delay, or may have severe behavioral problems.

Many individuals have hearing loss (easiest to be detected by parents), either conductive (in which pressure behind the ear drum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensory (in which tiny hair cells in the inner ear are damaged), or both.

Communicating hydrocephalus — in which the normal reabsorption of cerebrospinal fluid is blocked and causes increased pressure inside the head — is common in some of the mucopolysaccharidoses (the head is bigger than normal size). Surgically inserting a shunt into the brain can drain fluid.

The eye's cornea often becomes cloudy from intracellular storage, and glaucoma and degeneration of the retina also may affect the patient's vision.

Physical features

Physical symptoms generally include:

1. coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue), 
2. short stature with disproportionately short trunk (dwarfism), 
3. dysplasia (abnormal bone size and/or shape) and 
4. other skeletal irregularities, 
5. thickened skin, 
6. enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly), 
7. hernias, and 
8. excessive body hair growth. 
9. Short and often claw-like hands, 
10. progressive joint stiffness, and 
11. carpal tunnel syndrome can restrict hand mobility and function. 
12. Recurring respiratory infections (lung infections) are common, as are obstructive airway disease and obstructive sleep apnea (parents have to check on the child's breathing at night in case the child stops breathing).
13. Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.

Types

Seven distinct clinical types and numerous subtypes of the mucopolysaccharidoses have been identified.

Although each mucopolysaccharidosis (MPS) differs clinically, most patients generally experience a period of normal development followed by a decline in physical and/or mental function.

(Note: MPS-V and MPS-VIII are no longer in use as designations for any disease.)

Incidence

It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses.

Genetics and inheritance

It is an autosomal recessive disorder, meaning that only individuals inheriting the defective gene from both parents are affected. *

When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected.

The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the gene.


MPS Type II

1. Synonyms

MPS II
Hunter syndrome
Iduronate sulfatase deficiency

2. Cause of MPS II

MPS II is caused by lack of the enzyme iduronate sulfatase.

3. Genetic inheritance of MPS II

Hunter syndrome has two clinical subtypes and (since it shows X-linked recessive inheritance) is the only one of the mucopolysaccharidoses in which the mother alone can pass the defective gene to a son (mother to son inheritance; maternal inheritance).

* In MPS II or Hunter syndrome, the mother alone passes along the defective gene to a son.

http://en.wikipedia.org/wiki/File:Autorecessive.svg

4. Incidence of MPS II

The incidence of Hunter syndrome is estimated to be 1 in 100,000 to 150,000 male births.

Clinical exam, lab investigations and diagnosis

1. Clinical exam

Diagnosis often can be made through clinical examination and urine tests.

2. Urine tests

Excess mucopolysaccharides are excreted in the urine. Urine is sent to the clinical biochemistry lab for analysis. The urine sample is passed through a HPLC (high-performance liquid chromatography) and the chromatogram obtained indicates the accumulated mucopolysaccharide/glucosaminoglycan in this disease.

3. Enzyme assays

Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses.

4. Prenatal diagnosis & counselling

Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder.

Genetic counselling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.

Treatment and cost

Currently there is no known cure for these disorders.

Medical care is directed at treating systemic conditions and improving the person's quality of life.

Treatment is estimated to be approximately RM1million on 7 March 2014.

1. Muskeloskeletal system (limbs, bones and joints)

Physical therapy and daily exercise may delay joint problems and improve the ability to move.

The patient (toddler) usually crawls on all four by age 2, and is pushed around in a pram. The toddler holds on to the walls to stand up, or is pulled up by the hands.

2. Dietary changes

Changes to the diet will not prevent disease progression, but limiting milk, sugar, and dairy products has helped some individuals experiencing excessive mucus.

3. ENT (ear, nose and throat) intervention: tonsillectomy and adenoidectomy

Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea.

4. Sleep studies

Sleep studies can assess airway status and the possible need for nighttime oxygen.

5. Surgical intervention: endotracheal tube, correction of hernias, CSF drainage

Some patients may require surgical insertion of an endotracheal tube to aid breathing.

Surgery can also correct hernias.

Surgery can help drain excessive cerebrospinal fluid (CSF) from the brain, and free nerves and nerve roots compressed by skeletal and other abnormalities.

6. Ophthalmology (eye) surgery

Corneal transplants may improve vision among patients with significant corneal clouding.

7. Enzyme replacement therapy (ERT)

Enzyme replacement therapy (ERT) are currently in use or are being tested.

ERT has proven useful in reducing non-neurological symptoms and pain.

In July 2006, the United States Food and Drug Administration (USDA) approved a synthetic version of I2S produced by Shire Pharmaceuticals Group, called Elaprase, as a treatment for MPS type II (Hunter syndrome).

8. Bone marrow transplant (BMT)

Bone marrow transplantation (BMT) has limited success in treating the mucopolysaccharidoses.

BMT is a high-risk procedure and is usually performed only after family members receive extensive evaluation and counseling.

9. Umbilical cord blood transplantation (UCBT)

Umbilical cord blood transplantation (UCBT) has limited success in treating the mucopolysaccharidoses.

UCBT is a high-risk procedure and is usually performed only after family members receive extensive evaluation and counseling.

10. Neurological intervention

Abnormal physical characteristics, except for those affecting the skeleton and eyes, may be improved, but neurologic outcomes have varied.


External links
YouTube: Hope of Life ... Yusof Ashraf
Wikipedia: Mucopolysaccharidosis
MPS Australia
ClinicalTrials.gov
Hunter disease - clinical trial ends in Oct 2014