Introduction
Gargoylism, also known as Pfaundler-Hurler's Syndrome or Mucopolysaccharidosis type 1, is a genetic disorder that results in the buildup of glycosaminoglycans (formerly known as muchopolysaccharides) due to a deficiency of alpha-L iduronidase, an enzyme responsible for the degradation of mucopolysaccharides in lysosomes. Without this enzyme, a buildup of heparan sulfate and dermatan sulfate occurs in the body. Symptoms appear during childhood and early death can occur due to organ damage.
Etymology
The term "Gargoylism" derives from the unique facial features of child suffering from this syndrome: they are similar to the Gargoyles, carved stones grotesque, used in architecture during Hellenistic and Gotic period, usually made of granite, with a spout designed to convey water from a roof and away from the side of a building thereby preventing rainwater from running down masonry walls and eroding the mortar between.
The name Pfaundler-Hurler comes from Meinhard von Paundler and from Gertrud Hurler (1889-1965), a German Pediatrician and a Medical practitioner.
Pathogenesis
Heparan Sulfate
Mucopolysaccharidosis type I (MPS I) is a rare, inherited lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-L iduronidase. The disease is inherited in an autosomal recessive manner. The alpha-L-iduronidase deficiency results in an inability of the lysosome to break down GAG, namely dermatan sulfate and heparan sulfate. The alpha-L iduronidase hydrolizes alpha-L iduronosidic linkages in dermatan sulfate. This process is essential for normal growth and homeostasis of tissues. In this disease, GAG progressively accumulates in the lysosomes, ultimately causing cell, tissue, and organ dysfunction by largely unknown pathophysiological mechanisms. On a biochemical level, the alpha-L-iduronidase deficiency causes an increase in the urinary excretion of dermatan sulfate (DS) and heparan sulfate (HS) in patients with MPS I.
Hurler syndrome is caused by mutation in the gene IDUA that encodes alpha-L-iduronidase; it has been mapped to chromosome band 4p16.3. Many different mutations have been found at this locus, including mutations that cause MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), among others.
Epidemiology
Gargoylism is inherited in an autosomal recessive manner and affects both sexes.
Lifespan ranges from deathin childhood in the most severe form to adulthood in the least variant.
The birth prevalence is approximately 1 case per 100.000 births.
Laboratory Studies
The following studies are indicated in patients with suspected mucopolysaccharidosis type I (MPS I):
•Lymphocytes in the blood smears may be examined for abnormal cytoplasmic inclusions.
•Urinary levels of the mucopolysaccharides, dermatan sulfate (DS) and heparan sulfate (HS), are increased.
• Levels of a-L-iduronidase enzyme may be assayed in cultured fibroblasts and in leukocytes.
•Prenatal diagnosis of the enzyme level may also be made in amniotic cells and chorionic villi cells.
Manifestations
Clinical manifestations of mucopolysaccharidosis type I (MPS I) show a chronic multisystemic and progressive course. The disease is highly heterogeneous, spanning a spectrum of severity. Children with Hurler syndrome appear normal at birth and develop the characteristic appearance over the first years of life. Symptoms across the types include mental retardation, facial dysmorphism, corneal clouding, hepatomegaly, valvular heart disease, obstructive airway disease, developmental delay, hearing loss, skeletal deformities and joint stiffness. For patients with the more severe form of the disease, the most typical symptoms occur early in life. These patients typically have numerous progressively debilitating symptoms, including mental retardation. Their lifespan is less than 10 years. Individuals with less severe disease can have some of the same physical symptoms but generally retain normal intellect and stature, and may have a normal life span.
Facial dysmorphism or coarsened facial features
Coarsening of the facial features is usually the first abnormality detected. These features often first become apparent at age 3-6 months and may become progressively more evident. The head is large with bulging frontal bones. The skull is often scaphocephalic secondary to premature closure of the metopic and sagittal sutures. The nasal bridge is depressed with broad nasal tip and anteverted nostrils. The cheeks are full. The lips are enlarged, and the mouth is usually held open, particularly after age 3 years. Chronic nasal discharge is present. Eyes may be widely spaced, and eye sockets may be shallow, causing the eyes to slightly protrude.
The clinical presentation in less severe disease (MPS IS) may be limited to mild coarsening of facial features and prognathism. A large mouth with thick lips may develop.
Corneal clouding
As a result of glycosaminoglycan (GAG) storage, progressive corneal clouding is common in MPS I and can begin as early as the first year of life. Clouding of the cornea has a ground-glass appearance and may lead to blindness. Retinal degeneration is also common in MPS I.
Visceral involvement
Progressive hepatosplenomegaly is common in MPS I. GAG storage in the liver and spleen does not lead to organ dysfunction; however, organ size may be massive. Loose stools and diarrhea are episodic problems for some patients. Inguinal and umbilical hernias are common in MPS I. They are occasionally present at birth or develop within the first several months of life and are often one of the first clinical signs noted.
Skeletal involvement
Patients with severe disease demonstrate skeletal manifestations of MPS I early in life, by about age 6 months. At that time, widening of the ribs and mild bone abnormalities (detected by radiological methods) are common, particularly within the hip and ovoid vertebrae. At the clinical level, skeletal involvement does not become obvious until age 10-14 months, when a gibbus deformity of the back, or dorsolumbar kyphosis, is observed in patients with severe disease.
Eventually, progressive skeletal dysplasia involving all bones is seen in all types of MPS. The vertebrae may become progressively flattened and beaked, often leading to spinal deformity. Typically, the pelvis is poorly formed, with small femoral heads and coxa valga. Involvement of the femoral head leads to progressive and debilitating hip deformity. Clavicles may be short, thickened, and irregular (“oar-shaped”).
Length is often normal until about age 2 years, when growth stops; by age 3 years, height is less than the third percentile, and children may not grow taller than 120 cm.
Joint stiffness
The joints may become stiffened by age 2 years, and progressive arthropathy affects all joints. The hands take on a characteristic claw deformity, resulting from both phalangeal dysostosis and synovial thickening.
Carpal tunnel syndrome, a common complication in the MPSs, probably results from a combination of excessive lysosomal storage in the connective tissue of the flexor retinaculum and a deformity secondary to the underlying skeletal dysplasia.
Cardiopulmonary
Valvular disease, specifically aortic valve disease, may be seen in these patients. Frequent upper and lower respiratory tract infections are common. Respiratory obstruction occurs secondary to enlargement of tonsils and adenoids, chronic hearing loss, and enlarged tongue. However, in mild forms, the intellectual level is normal. Usually death occurs due to myocardial infarction and heart failure.
Development
In severe forms of MPS I, developmental delay is often apparent by age 12-24 months, with a maximum functional age of 2-4 years, followed by progressive deterioration. Most children develop limited language because of developmental delay.
Others
The neck is short, and odontoid hypoplasia is noted. Vertebral subluxation with cord compression can occur. Body hair may be coarser than usual, and the skin may be thicker.
Medical Care
Because of multisystemic involvement in patients with mucopolysaccharidosis type I (MPS I), treatment is multidisciplinary and encompasses both the curative and palliative elements. Regular evaluation at a major center with special interest and expertise in the management of the disease is important.
Enzyme replacement therapy with laronidase may provide clinically important benefits such as improved pulmonary function and walking ability and reduction of excess carbohydrates stored in organs.
Surgical Care
Corrective surgery may be necessary for patients with mucopolysaccharidosis type I (MPS I) who have joint contractures or foot and hand deformities. Corneal transplants may be required if vision problems become severe.
Enzyme, Replacement Therapy
Replacing the deficient enzyme may improve symptoms and delay disease-induced complications. Laronidase is indicated to treat MPS I (Hurler syndrome and Hurler-Scheie syndrome). Used to increase catabolism of GAG, which accumulates with MPS I. Treatment has been shown to improve walking capacity and pulmonary function. Laronidase is a polymorphic variant of the human enzyme a-L-iduronidase produced by recombinant DNA technology.
