Sanfilippo Syndrome (Mucopolysaccharidosis Type III) Clinical Presentation

Updated: Apr 19, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. In all subtypes of this syndrome, CNS disease predominates, with less skeletal and soft tissue involvement compared with the other mucopolysaccharidoses (MPSs). Type IIIA has the most CNS involvement. This subtype represents the most severe form of Sanfilippo syndrome with an earlier and more rapid onset of symptoms than others within mucopolysaccharidosis III. Note the following:

  • Onset of symptoms usually occurs between age 2 and 6 years in a previously healthy-appearing child. Some patients may show developmental delays in infancy. Growth parameters are normal or accelerated prior to age 3 years, with growth delays seen in older children.

  • Initial symptoms present as behavioral changes. Patients are hyperactive and show aggressive and destructive behaviors. More aggressive behaviors have been reported in females when compared with male patients.

  • Sleep disturbances are common.

  • Mental development slows after the toddler years; then, progressive deterioration occurs in regard to gait and speech articulation. Some patients may never speak.

  • Seizures may occur but usually are well-controlled with medication.

  • During the early school years, symptoms worsen and patients show shortened attention spans and difficulties with concentration. Mental and physical disabilities prevent most children from progressing in their school academics.

  • By age 10 years, patients are severely limited in their activities and movement. Most children with type IIIA have severe neurologic impairment by age 6 years. Recurrent or chronic diarrhea occurs in mucopolysaccharidosis III patients. The etiology for this abnormal gut motility is thought to be due to lysosomal glycosaminoglycans (GAG) storage in the neurons of the myenteric plexus of the small intestine.

  • Respiratory compromise can occur and is related to airway obstruction due to anatomic changes, excessive thick secretions, and neurologic impairment. Upper respiratory tract infections and sinopulmonary disease are common.



The striking clinical features of coarse facial features and skeletal abnormalities seen in the mucopolysaccharidoses are not as apparent in patients with mucopolysaccharidosis III. Mild facial coarsening may be present, and the skeletal differences are typically subtle. Corneal clouding, as seen in the other mucopolysaccharidoses, is not usually present. However, classic clinical features are an abundance of coarse facial and body hair (hirsutism). Note the following [11] :

Head, eyes, ears, nose, and throat (HEENT)

  • Mild coarse facial features

  • Synophrys

  • Clear corneas (some patients may have mild corneal opacities)

  • Hearing loss with speech delay


  • Asymmetric septal hypertrophy

  • Cardiomegaly


  • Mild hepatomegaly

  • Mild splenomegaly


  • Inguinal hernia,

  • Umbilical hernia


  • Dense calvaria

  • Mild dysostosis multiplex (constellation of characteristic skeletal abnormalities seen in mucopolysaccharidoses)

  • Joint stiffness


  • Mentally challenged

  • Behavioral and sleep disturbances

  • Severe progressive neurologic degeneration



The deficiency or lack of a specific lysosomal enzyme is responsible for each subtype of Sanfilippo syndrome. Specifically, for type IIIA, the enzyme is heparan sulfate sulfatase; for type IIIB, the enzyme is N -acetyl-alpha-D-glucosaminidase; for type IIIC, the enzyme is acetyl-CoA:alpha-glucosaminide acetyltransferase; and for type IIID, the enzyme is N -acetylglucosamine-6-sulfatase.

Heparan sulfate accumulates in the lysosomes of tissues and organs, causing the diverse morphological abnormalities seen in mucopolysaccharidosis type III patients. Large amounts of heparan sulfate are excreted in the urine.

The enzymatic defects defining all subtypes of Sanfilippo syndrome are inherited as autosomal recessive disorders; this genetic inheritance also is true of the other mucopolysaccharidoses, except for mucopolysaccharidosis type II or Hunter syndrome, which has X-linked recessive inheritance. Due to the autosomal recessive inheritance pattern, biological parents of an affected child have a 25% risk of having another affected child with each pregnancy.

The gene mutations for the 4 different types have been mapped on the human genome. Their chromosomal or cytogenetic locations are as follows [11] :

  • Type IIIA - 17q25.3

  • Type IIIB - 17q21.2

  • Type IIIC - 8p11.21

  • Type IIID - 12q14.3