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