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Maroteaux Lamy Syndrome

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NORD is very grateful to Roberto Giugliani, MD, PhD, MSc, Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Brazil, for assistance in the preparation of this report.

Synonyms of Maroteaux Lamy Syndrome

Disorder Subdivisions

General Discussion

Summary
Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a rare genetic disorder characterized by complete or partial lack of activity of the enzyme arylsulfatase B (also called N-acetylgalactosamine-4-sulfatase). Deficiency or absence of this enzyme activity leads to the accumulation of complex carbohydrates called glycosaminoglycans (previously known as mucopolysaccharides) in the body. Abnormal accumulation of mucopolysaccharides leads to progressive involvement of multiple organ systems. The symptoms and severity of Maroteaux-Lamy syndrome can vary dramatically from one person to another; some individuals only develop mild symptoms, while others develop severe, even life-threatening complications. Common symptoms can include coarse facial features, corneal clouding, joint abnormalities, various skeletal malformations, an abnormally enlarged liver and/or spleen (hepatosplenomegaly), and hearing loss. Cardiac disease and restrictive pulmonary disease can also occur. Intelligence is usually not affected. In 2005, the Food and Drug Administration (FDA) approved the enzyme replacement therapy known as Naglazyme® for the treatment of Maroteaux-Lamy syndrome. Maroteaux-Lamy syndrome occurs due to mutations in the ARSB gene and is inherited as an autosomal recessive disorder.

Introduction
The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. More than 50 lysosomal storage disorders have been identified so far. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular metabolites, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates known as mucopolysaccharides or glycosaminoglycans in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of MPS. These disorders, with one exception (MPS type II), are inherited in an autosomal recessive manner. Maroteaux-Lamy syndrome was named from the two French physicians who first described this disorder in the medical literature in 1963.

Symptoms

The symptoms, onset and rate of progression of Maroteaux-Lamy syndrome vary greatly from one person to another. The disorder can be thought of as a spectrum or continuum of disease. Some individuals may only have a few symptoms and others may have serious symptoms affecting several different organ systems simultaneously. Maroteaux-Lamy syndrome can potentially cause life-threatening complications. Some individuals will have severe symptoms during infancy, while others have slowly progressive symptoms that develop over the course of multiple decades.

The variable nature of Maroteaux-Lamy syndrome means that most affected individuals will not have all of the symptoms potentially associated with the disorder. Individuals with this disorder can differ from one another dramatically. Parents should talk to their children’s physician and medical team about their child’s specific case, associated symptoms and overall prognosis. Most affected individuals come to medical attention during middle childhood.

Rapidly progressive Maroteaux-Lamy syndrome is associated with an onset before three years of age. Affected individuals may develop walking problems (impaired mobility) by the age of 10 and experience delayed or absence of puberty. These individuals may be at risk of heart failure by second or third decades of life.

Slowly progressive disease is characterized by later onset. A diagnosis is usually obtained after five years of age, most often during the second or third decade. Despite a slower progression, individuals may still develop a decrease in overall function and ability by their late teen-aged years. Most individuals with Maroteaux-Lamy syndrome will develop serious complications at some point such as joint degeneration, cardiovascular disease, reduced pulmonary function or sleep apnea.

Intelligence is usually not affected in Maroteaux-Lamy syndrome. However, learning difficulties may be present as a consequence of other problems associated with the disorder (e.g., hearing loss).

Affected individuals often exhibit short stature due to growth restrictions. Short stature is described as disproportionate because the trunk may be shorter than the legs. In severe cases, final height may be under 4 feet (120 centimeters). Degenerative joint disease is also common and can lead to the development of multiple joint contractures. A contracture occurs when thickening or shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected joint.

Individuals with Maroteaux-Lamy syndrome may be described as having ‘dysostosis multiplex’ a group of skeletal abnormalities that can be seen on x-ray examination. These abnormalities include thickened, short bones of the palm of the hands (metacarpals), underdeveloped (hypoplastic) and irregular wrist bones (carpal bones), abnormal ankle bones (tarsal bones), malformation (dysplasia) of the head of the thighbone (dysplastic femoral head), severe malformation of the hip, abnormalities of the ribs and spine, thickened collarbones (clavicles), and underdevelopment of the bones of the forearm (ulna and radius). Additional skeletal malformations may include a prominent breastbone (pectus carinatum), abnormal curvature of the spine, and knock-knees (genu valgum).

Skeletal malformations can be associated with a variety of complications. Affected individuals may develop pain, especially of the joints and hip, spinal cord compression, an abnormal manner of walking (gait), or difficulty walking. Affected joints may have a limited range of motion making daily tasks difficult. For example, the ability to fully move the shoulders may make simple tasks such as putting on a shirt or combing hair difficult.

Distinctive facial features usually do not occur in individuals with mild forms of the disorder. Individuals with severe forms often share distinctive facial characteristics and these individuals may resemble one another in facial appearance. Such characteristics include chubby faces, thickened lips due to the overgrowth of the gums (gingival hypertrophy), an unusually prominent forehead (frontal bossing), and a broad, flattened bridge of the nose. In some cases, the tongue may be enlarged (macroglossia). Abnormal growth of hair on the face or the body may also occur (hirsutism). Some individuals have a short, stiff neck.

Clouding (opacity) of the thin transparent covering of the front of the eye (cornea) may also occur. If corneal clouding is severe the patient may present vision loss, particularly in dim light. Some individuals may sensitive to bright lights. If the nerve-rich lining the back of the eyes (retina) is involved, affected individuals may have reduced peripheral vision or develop night blindness. In some cases, increased pressure within the eye (glaucoma) may also develop. Increased intraocular pressure may cause swelling of the optic disc (papilledema). Less commonly, additional eye abnormalities may occur including degeneration of the nerve that transmits visual information from the retina to the brain (optic nerve atrophy).

Affected individuals may experience chronic watery, mucous discharge from nose (rhinorrhea), frequent sinus infections, and middle ear infections (otitis media). Hearing loss is common. Hearing loss may be due to failure of sound to be conducted from the outer ear trough the eardrum and tiny bones of the middle ear (conductive hearing loss) or may be due to damage to the inner ear or the nerves that transmit sound from the inner ear to the brain (sensorineural). In rare cases, hearing loss may be due to a combination of both problems (mixed hearing loss).

Abnormalities of the heart are common in children with Maroteaux-Lamy syndrome. Symptoms associated with heart disease can include breathlessness, cough, wheezing, excessive sweating and recurrent chest infections. Affected children may also exhibit failure to thrive and difficulty feeding. High blood pressure (hypertension) is also common. Cardiac abnormalities can include narrowing (stenosis) and insufficiency of certain valves of the heart including the aortic, the mitral, and the tricuspid valves. Heart valves ensure that blood flows in only one direction within the heart. When a valve is damaged or malformed, blood can flow backward from one chamber back into another. Slowly progressive valvar heart disease can be present for years without causing symptoms. Eventually, valvar heart disease can cause a heart murmur. Narrowing of the heat valves can progressively make it more difficult for the heart to pump blood and can eventually result in heart failure.

Additional heart abnormalities can include disease or weakening of the heart muscle (cardiomyopathy) and endocardial fibroelastosis. Cardiomyopathy can be associated with a progressive inability to pump blood, fatigue, heart block, and irregular heartbeats (tachycardia). Endocardial fibroelastosis is a condition characterized by thickening of the endocardium of the ventricles. The endocardium is the innermost layer of tissue that surrounds the heart. These conditions can make it more difficult for the heart to pump blood effectively and can eventually cause heart failure and sudden cardiac death.

The lungs and other parts of the pulmonary system may be affected in some cases. The storage of mucopolysaccharides may cause affected tissue to swell, which can obstruct various airways in the body, resulting in a high-pitched, loud respiratory sound (stridor) and airway compromise. Thick, mucous secretions can further clog the airways. The chest may become rigid, preventing the lungs from taking in sufficient amounts of air. Obstructive and restrictive lung disease can cause breathlessness, reduced endurance, recurrent episodes of pneumonia, and/or sleep apnea. Some affected infants have abnormal softening and weakening of the cartilage of the trachea (windpipe) so that the walls of the trachea are floppy instead of rigid (tracheomalacia). This is often mild, but can be severe, leading to collapse of the air passage. Tracheomalacia can contribute to breathing difficulties and may precipitate respiratory arrest. In some cases, the tonsils and adenoids may become enlarged narrowing the airway in the throat and contributing to breathing difficulties.

Abnormal enlargement of the liver (hepatomegaly) is common in individuals with Maroteaux-Lamy syndrome. Less often, the spleen may also be enlarged (splenomegaly). Hernias, conditions in which the abdominal membrane or contents protrude through a weak point in the abdominal wall, are also common. Umbilical hernias occur when the contents protrude from behind the bellybutton; inguinal hernias occur in the groin area. Some affected individuals have a protruding or bulging abdomen because of weakened muscles and/or hepatosplenomegaly.

Some affected individuals may develop hydrocephalus, a condition in which the accumulation of excess cerebrospinal fluid in the skull causes increased pressure on the brain, potentially causing a variety of symptoms.

Another common symptom associated with Maroteaux-Lamy syndrome is carpal tunnel syndrome, a condition caused by compression of a nerve running through the wrist. Symptoms usually begin as chronic tingling, burning or numbness in the wrist. Eventually, it can progress to cause sharp, piercing pain. Less often, tarsal tunnel syndrome, a similar condition affecting the ankle, may also occur.

Certain gastrointestinal symptoms including loose stools, diarrhea, or severe constipation have also been reported in individuals with Maroteaux-Lamy syndrome.

Causes

Maroteaux-Lamy syndrome is caused by mutations in the ARSB gene. Genes provide instructions for making proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Investigators have determined that the ARSB gene is located on the long arm (q) of chromosome 5 (5q13-q14). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 5q13-q14" refers to bands 13-14 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The ARSB gene is related to (encodes) the lysosomal enzyme arylsulfatase B. Deficiency of this enzyme results in the accumulation of dermatan sulfate, a type of mucopolysaccharide, in the cells of various tissues of the body. More than 130 different mutations in the ARSB gene have been identified. Certain mutations are more likely to be associated with specific symptoms and/or severity (genotype-phenotype correlation).

The ARSB mutation is inherited as an autosomal recessive disorder. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutation that causes the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% in each pregnancy. The risk to have a child who is a carrier like the parents is 50% in each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Affected Populations

Maroteaux-Lamy syndrome affects males and females in equal proportion. The exact incidence and prevalence of the disorder is unknown. The prevalence of all forms of MPS is estimated to be from one in 43,261 to one in 1,505,160 births. However, because MPS disorders, especially milder forms, often go unrecognized, these disorders are underdiagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of Maroteaux-Lamy syndrome. Comparisons may be useful for a differential diagnosis.

Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the mildest form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and corneal clouding that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five. (For more information on this disorder, choose "Scheie" as your search term in the Rare Disease Database.)

Multiple sulfatase deficiency is an extremely rare hereditary metabolic disorder in which all of the known sulfatase enzymes (thought to be seven in number) are deficient or inoperative. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak at the same time of other children. The specific symptoms and severity of this disorder can vary greatly from one person to another. Multiple sulfatase deficiency is inherited in an autosomal recessive manner. (For more information on this disorder, choose "multiple sulfatase deficiency" as your search term in the Rare Disease Database.)

Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose "lysosomal storage diseases" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of Maroteaux-Lamy syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.

Clinical Testing and Workup
In individuals suspected of Maroteaux-Lamy syndrome the urine will be examined to assess the levels of the mucopolysaccharides. Elevated levels of dermatan sulfate are indicative of Maroteaux-Lamy syndrome. In addition, a blood sample may be taken to measure the enzyme activity of arylsulfatase B because deficient or absent activity of this enzyme is also indicative of the disorder. Certain types of skin cells (skin fibroblasts) can also be examined to determine arylsulfatase B enzyme activity.

Molecular genetic testing can confirm a diagnosis of Maroteaux-Lamy syndrome. Molecular genetic testing can detect mutations in the gene ARSB, but is available only at specialized laboratories.

Treatment
The treatment of Maroteaux-Lamy syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, orthopedists, cardiologists, dental specialists, ear-nose-throat specialists (otorhinolaryngologists), specialists who deal with diseases of the lungs and respiratory tract (pulmonologists), specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan the treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.

In 2005, the U.S. Food and Drug Administration (FDA) approved the orphan drug Naglazyme® (galsulfase) for the treatment of individuals with Maroteaux-Lamy syndrome. Naglazyme is an enzyme replacement therapy (ERT), a therapy in which the missing or inactive enzyme is replaced with a genetically engineered (recombinant) version. For more information, contact:

BioMarin Pharmaceutical, Inc.
105 Digital Drive
Novato, CA 94949
Telephone: (415) 506-6700
Fax: (415) 382-7889
Patient & Physician Support; (866) 906-6100
www.naglazyme.com

Additional treatment is symptomatic and supportive. For example, surgery may be necessary to treat various abnormalities associated with Maroteaux-Lamy syndrome including carpal tunnel syndrome, skeletal malformations, spinal cord compression, degeneration of the hip, and hernias. Heart valve replacement may be necessary in some cases. Surgical removal of the tonsils and/or adenoids may be recommended. Tracheomalacia is usually treated by noninvasive measures, but in rare cases can require surgical intervention.

Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess of cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. A corneal transplantation can be performed for individuals with severe corneal clouding. Individuals with conductive hearing loss may experience the accumulation of a sticky fluid within the middle ear (glue ear). This is treated with a procedure called a myringotomy, in which a thin incision is made in the eardrum to release the fluid. There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing.

Certain medications can be used to treat heart abnormalities, asthma-like episodes, and chronic infections. Anti-inflammatory medications may be of benefit. Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well.

Some affected individuals may undergo a sleep study, in which people are evaluated on how well they sleep and how well their body responds to sleep problems. Sleep apnea may be treated with continuous positive airway pressure (CPAP), which involves the use of a mask or similar device to deliver mild air pressure to keep airways open. In some cases, a similar treatment method known as bilevel positive airway pressure (BPAP) may be used. BPAP devices provide more pressure when you breathe in and less pressure when you breathe out.

Physical therapy and exercise may improve joint stiffness. Speech therapy may help children with hearing loss communicate effectively. Nutritional counseling and occupational therapy may also beneficial.

Investigational Therapies

Hematopoietic stem cell transplantation (HSCT) as a way to replace the defective enzymes has been studied as a treatment for individuals with mucopolysaccharidoses. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in the long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells -- red cells, white cells, or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individuals with marrow from a person who does not have a particular disorder. The healthy cells produced by the new marrow contain sufficient levels of the lysosomal enzyme arylsulfatase B. The effectiveness of HSCT has varied greatly. Physical characteristics may improve, such as cloudy corneas may become clear, the size of an enlarged liver or spleen may be reduced, and mucopolysaccharides levels may drop. Other symptoms are unaffected. The effect on neurological symptoms varies considerably. HSCT in Maroteaux-Lamy syndrome has only been tried in a handful of cases. Because HSCT is a procedure that carries significant risks, it should only be considered in selected cases. More research is necessary to determine the long-term safety and effectiveness of HSCT for individuals with Maroteaux-Lamy syndrome.

Gene therapy is also being studied as another approach to therapy for individuals with mucopolysaccharidoses such as Maroteaux-Lamy syndrome. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme and prevent the development and progression of the disease. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a ‘cure’. However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

Maroteaux Lamy Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Clarke JTR. Mucopolysaccharide Storage (MPS) Diseases. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:474-476.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:135-137.

JOURNAL ARTICLES
Jester S, Larsson J, Eklund EA, et al. Haploidentifical stem cell transplantation in two children with mucopolysaccharidosis VI: clinical and biochemical outcome. Orphanet J Rare Dis. 2013;8:34. http://www.ncbi.nlm.nih.gov/pubmed/24107440

Brands MM, Oussoren E, Ruijter GJ. Up to five years experience with 11 mucopolysaccharidosis type VI patients. Mol Genet Metab. 2013;109:70-76. http://www.ncbi.nlm.nih.gov/pubmed/23523338

Brands MM, Hoogeveen-Westerveld M, Kroos MA, et al. Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase. Orphanet J Rare Dis. 2013;8:51. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637222/

Braulin E, Rosenfeld H, Kampmann C, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy. J Inherit Metab Dis. 2013;36:385-394. http://www.ncbi.nlm.nih.gov/pubmed/22669363

Jurecka A, Golda A, Opoka-Winiarska V, et al. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) with a predominantly cardiac phenotype. Mol Genet Metab. 2011;104:695-699. http://www.ncbi.nlm.nih.gov/pubmed/21917494

Valayannopoulos V, Nicely H, Harmatz P, Tuberville S. Orphanet J Rare Dis. 2010;5:5. http://www.ojrd.com/content/5/1/5

Decker C, Yu ZJ, Giugliani R, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase. J Pediatr Rehabil Med. 2010;3:89-100. http://www.ncbi.nlm.nih.gov/pubmed/20634905

Giugliani R, Federhen A, Rojas MV, et al. Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment. Genet Mol Biol. 2010;33:589-604. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036139/

Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics. 2007;120:405-418. http://www.ncbi.nlm.nih.gov/pubmed/17671068

Karageorgos L, Brooks DA, Pollard A, et al. Mutational analysis of 105 mucopolysaccharidosis type VI patients. Hum Mutat. 2007;28:897-903. http://www.ncbi.nlm.nih.gov/pubmed/17458871

Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144:S27-S34. http://www.ncbi.nlm.nih.gov/pubmed/15126981

INTERNET
Harmatz P, Nicely H, Tuberville S, Valayannopoulos V. Mucopolysaccharidosis type 6. Orphanet Encyclopedia, April 2010. Available at: http://www.orpha.net Accessed December 15, 2013.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:253200; Last Update:10/04/2012. Available at: http://omim.org/entry/253200 Accessed December 15, 2013.

Report last updated: 2014/03/05 00:00:00 GMT+0