Hurler Syndrome

Genetically transmitted lysosomal storage disease resulting in accumulation of acid mucopolysaccharides in the central nervous system and peripheral tissues characterized by coarse facies (gargoyle-like), profound mental retardation, considerable hepatomegaly, hernias, enlarged tongue, skeletal disorders (kyphoscoliosis), dwarfism, and respiratory and cardiac impairment.

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Alpha-L-Iduronidase Deficiency Syndrome; Dysostosis Multiplex; Dysostotic Idiocy; Johnie McL Disease; Hurler-Pfaundler Syndrome; Gargoylism; Lipochondrodystrophy; Mucopolysaccharidosis type IH; Pfaundler-Hurler Syndrome; Thompson Syndrome; Hurler-Scheie Syndrome.

Inborn error of metabolism of GAGs. First described in 1919 by Gertrud Hurler, a German pediatrician (1889-1965).

1:10,000-100,000 live births.

Autosomal recessive. Defective gene responsible for the production of alpha-l-iduronidase is located at chromosome 4p16.3. No sex predilection.

Deficiency of alpha-l-iduronidase leads to tissue accumulation of dermatan and heparan sulfates. The disease leads to severe disorders within the extracellular matrix, which is made up of several proteins and sugars, including proteoglycan, the catabolism of which yields dermatan and heparin sulfates.

Typical phenotype. Increased urinary excretion of dermatan and heparan sulfates. Deficiency of alpha-l-iduronidase activity in leukocytes and cultured skin fibroblasts. Prenatal diagnosis available (deficiency of enzyme activity in cultured chorionic villi or amniocytes, increased GAGs in amniotic fluid). Carrier detection possible using 4-methylumbelliferyl-α-iduronate.

Infants appear normal at birth but develop typical phenotype by the end of first year of life, including coarse facial features, large, deformed skull, short stature, kyphoscoliosis, multiple skeletal abnormalities, clouded corneas, hernias, and hepatosplenomegaly. As the disease progresses, there may be narrowing of the coronary arteries and thickening of the cardiac valves and myocardium leading to heart failure. The course of the disease is associated with a progressive deterioration with mental retardation. Death from cardiorespiratory failure commonly occurs in the early teens.

Assess cardiorespiratory status carefully and obtain appropriate investigations, for example, chest radiograph, echocardiogram. Assess airway and degree of cervical spine instability. Check medical history for evidence of airway obstruction during sleep. Treat intercurrent respiratory infections.

Children with Hurler syndrome frequently present difficulties with airway management that increases with age. About half of direct laryngoscopy and tracheal intubations are very difficult, and securing the airway may fail in 10%. The airway is compromised by accumulation of mucopolysaccharides in the soft tissues of the head and neck. Airway obstruction may occur during induction of anesthesia, and face-mask fit may be poor. The trachea may be narrowed or flattened, necessitating the availability of a range of endotracheal tube sizes. There is frequently severe limitation of movement of the cervical spine and restrictive lung disease. Progressive cardiac failure or pulmonary hypertension occur in some patients, further complicating management. The skin is thickened, and venous cannulation may be difficult. Because of the progressive nature of the disease, previous uneventful anesthesia cannot be relied upon as reassurance. If the airway is predicted to be difficult, the aim should be to maintain spontaneous breathing during induction of anesthesia, with halothane or sevoflurane considered the agents of choice. The trachea must be secured, lung ventilation confirmed with the presence of endtidal CO2 and by chest auscultation before any neuromuscular blockade agents is given. Antisialagogue premedication is indicated. The laryngeal mask has been useful for airway maintenance in these children and serves as a conduit for intubation, aided if necessary by a fiberoptic bronchoscope. Attempts at nasal intubation may be hindered by narrowing of the nasal airway. In some cases, emergent tracheostomy has been necessary to secure the airway. Regional anesthesia alone for surgery is often impaired by mental retardation. Postoperatively, there are risks of airway obstruction, particularly if opioids are used. Pain relief may be provided using local anesthetic techniques or nonsteroidal antiinflammatory drugs (NSAIDs). Be prepared to support ventilation in the postoperative period, especially to facilitate proper pain management.

Avoid sedating drugs in the postoperative period in patients where the airway is not secured. There are no specific implications with this condition; however, the underlying cardiopulmonary status may dictate each indication.

Gangliosidosis (GM1) Type I: Autosomal recessive lysosomal storage disease characterized by coarse facies and progressive neurodegeneration. It is caused by an accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan. There is a deficient activity of lysosomal enzyme β-galactosidase. Gene map locus is 3p21.33. Pseudo-Hurler polydystrophy is milder than mucolipidosis type II or I cell disease (see I-Cell Disease) with a later onset (2-4 years), slower progression, and possible survival into adulthood. It is caused by a mutation in the UDP-N-acetylglucosamine-1 phosphotransferase gene located on chromosome 4q21-q23. The genetics and pathophysiology is similar to that of mucolipidosis type II. Affected patients have clinical features resembling those of mucopolysaccharidoses types I and VI but without mucopolysacchariduria. Joint stiffness, scoliosis, and skeletal dystrophy are present. Cardiac valvular lesions are present, of which aortic insufficiency is most common. Although puberty is normal, approximately 50% of reported cases have mild mental retardation. Although type III is a milder illness, all the anesthetic considerations—including difficult mask ventilation, direct laryngoscopy, and tracheal intubation must be considered. The presence of odontoid hypoplasia with the possibility of an unstable neck must be taken for granted in all patients. The association of thickened trachea wall necessitating smaller endotracheal tube and the presence of obstructive sleep apnea are very important features. The clinical presentation is very similar to patients affected with I cell disease.

Mucopolysaccharidosis Type II (Hunter Syndrome): X-linked lysosomal storage disease characterized by accumulation of acid mucopolysaccharides (heparan and dermatan sulfates) in the central nervous system and peripheral tissues, affecting only male children and resulting in severe neurologic impairment. The defective gene is iduronate-2-sulfatase (IDS). Gene map location is Xq27.3-q28.

I-Cell Disease: Rare inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities, and mental retardation. The symptoms of I cell disease are similar to, but more severe, than those of Hurler syndrome. The onset of age is during infancy (6-10 months). Craniofacial abnormalities include coarse facial features, depressed nasal bridge, long and narrow head, unusually high and narrow forehead, and/or epicanthal folds. Skeletal malformations including scoliosis, kyphosis, short neck, congenital hip dislocation, lumbar gibbus (swelling of the top portion of the spine), and limited mobility of the shoulders. Other clinical features include hypotonia, dwarfism, hepatomegaly, umbilical hernia, and inguinal hernia.