Hearing loss |
Expert comments and/or parental concerns
-
Most MPS III patients do not fail the hearing test on newborn screening. Therefore, the hearing test on newborn screening is not always a reliable predictor.
-
Children with another cause of hearing loss are generally more engaged and attempt to compensate for hearing loss by actively trying to find other signals, although lack of engagement might also be related to developmental disorders other than MPS III.
-
An auditory brainstem response (ABR) could be informative. An ABR can demonstrate prolonged latencies in MPS III patients compared to the latencies of others with similar configurations of hearing loss. Typically, ABRs are coordinated with other procedures for which the patient is already under anesthesia. Tympanometry is usually conducted in conjunction with ABRs.
-
Although hearing loss in MPS III is typically sensorineural, conductive components might be present due to recurring ear infections or middle ear disease which might mask mild sensorineural hearing loss. Sensorineural hearing loss typically starts as a mild, sloping high-frequency hearing loss that progresses over time.
Supporting medical literature
-
The type of hearing loss, conductive versus sensorineural, can give clues regarding the potential presence of MPS III, which is typically characterized by sensorineural hearing loss and altered ABRs 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8 https://doi.org/10.1007/s10545-013-9661-...
,3131. Zanetti D, Vezzani M, Di Berardino F, et al. Characterization of hearing loss in children with mucopolysaccharidosis. An Excursus into Hearing Loss. London, UK: IntechOpen; 2018..
|
Craniosynostosis |
Expert comments and/or parental concerns
-
Craniosynostosis was identified by the experts as potential early symptom, although it is not a common presentation in MPS III in comparison to MPS I, II, and VI.
Supporting medical literature
-
Craniosynostosis affects the majority of MPS patients regardless of the MPS type 3232. Oussoren E, Mathijssen IMJ, Wagenmakers M, et al. Craniosynostosis affects the majority of mucopolysaccharidosis patients and can contribute to increased intracranial pressure. J Inherit Metab Dis. 2018;41(6):1247-1258. doi:10.1007/s10545-018-0212-1 https://doi.org/10.1007/s10545-018-0212-...
.
|
Sleep disturbance |
Expert comments and/or parental concerns
Supporting medical literature
-
Fraser et al. showed that 91.5% of children with MPS III suffer from sleep disturbance (age of onset: birth to 22 years). Sleep disturbance occurs more frequently in MPS III patients versus their unaffected siblings 88. Fraser J, Gason AA, Wraith JE and Delatycki MB. Sleep disturbance in Sanfilippo syndrome: a parental questionnaire study. Arch Dis Child. 2005;90(12): 1239-1242. doi:10.1136/adc.2004.065482 https://doi.org/10.1136/adc.2004.065482...
.
|
ENT problems |
Expert comments and/or parental concerns
Supporting medical literature
-
Evidence confirms the presence of chronic sinusitis and otitis media. 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
,1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8 https://doi.org/10.1007/s10545-013-9661-...
,3333. Yodoshi T and Hurt TL. Avoiding diagnostic delay for mucopolysaccharidosis IIIB: do not overlook common clues such as wheezing and otitis media. BMJ Case Rep. 2018;2018:bcr-2018-224412. doi:10.1136/bcr-2018-224412 https://doi.org/10.1136/bcr-2018-224412...
.
|
Gastrointestinal problems |
Expert comments and/or parental concerns
Supporting medical literature
-
In a natural history cohort of Spanish MPS III patients, recurrent diarrhea was present in 50% of cases before diagnosis 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
.
-
There is no medical literature supportive of the tendency to overeat in MPS III patients. However, MPS IIIA mice exhibited greater bodyweight gain than controls, which was explained by abnormalities in gastrointestinal structure and function. Whether these findings translate to humans is unclear 3434. Roberts AL, Howarth GS, Liaw WC, et al. Gastrointestinal pathology in a mouse model of mucopolysaccharidosis type IIIA. J Cell Physiol. 2009;219(2):259-64. doi:10.1002/jcp.21682 https://doi.org/10.1002/jcp.21682...
.
|
Umbilical or inguinal hernia |
Expert comments and/or parental concerns
Supporting medical literature
-
Umbilical hernia and inguinal hernia were reported in 22% and 7% of MPS III patients at a median age of 1 month (range 0-8 months) and 1.6 years (range 0-3 years), respectively 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
. However, umbilical hernias frequently occur in newborns affecting an estimated 10-30% of all white children at birth and an estimated 23-85% of children in the African population, while inguinal hernias occur in 0.8% to 5% of infants 3535. Bowling K, Hart N, Cox P and Srinivas G. Management of paediatric hernia. BMJ. 2017;359:j4484. doi:10.1136/bmj.j4484 https://doi.org/10.1136/bmj.j4484...
.
|
Hirsutism |
Expert comments and/or parental concerns
Supporting medical literature
-
Hirsutism was reported as the most prevalent physical symptom (93%) and the second most common initial sign (64%) in a Taiwanese cohort of MPS III patients 3636. Lin HY, Chuang CK, Lee CL, et al. Mucopolysaccharidosis III in Taiwan: natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21-year period. Am J Med Genet A. 2018;176(9): 1799-1809. doi:10.1002/ajmg.a.40351 https://doi.org/10.1002/ajmg.a.40351...
.
|
Facial abnormalities |
Expert comments and/or parental concerns
-
Frontal bossing, coarse facial features, puffiness underneath the eyes and eyebrows, and a particular lip morphology with a narrow upper lip and a thick lower lip were identified.
-
Macrocephaly, especially when presented as early as at birth.
Supporting medical literature
-
Coarse facial features were present before diagnosis in 78% of MPS III patients in a Spanish natural history cohort 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
.
-
Head circumference is increased within the first 2 years of life until physical maturity and is followed by a gradual decline likely related to the progressive loss of brain tissue 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8 https://doi.org/10.1007/s10545-013-9661-...
,1717. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007;120(5):e1255-e1261. doi:10.1542/peds.2007-0282 https://doi.org/10.1542/peds.2007-0282...
,2727. Muschol NM, Pape D, Kossow K, et al. Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III). Orphanet J Rare Dis. 2019;14:93. doi:10.1186/s13023-019-1065-x https://doi.org/10.1186/s13023-019-1065-...
,3737. de Ruijter J, Broere L, Mulder MF, et al. Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). J Inherit Metab Dis. 2014;37(3):447-454. doi:10.1007/s10545-013-9658-3 https://doi.org/10.1007/s10545-013-9658-...
.
|
Abnormal growth |
Expert comments and/or parental concerns
-
Physically, MPS III patients might appear older than their actual age, but because of their lower intellectual ability, hyperactivity, and balance issues, their physical and intellectual maturity is often incongruent.
Supporting medical literature
-
No normal Gaussian distribution of the growth curve. MPS III patients are in the highest percentile of the growth curve 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8 https://doi.org/10.1007/s10545-013-9661-...
,3737. de Ruijter J, Broere L, Mulder MF, et al. Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). J Inherit Metab Dis. 2014;37(3):447-454. doi:10.1007/s10545-013-9658-3 https://doi.org/10.1007/s10545-013-9658-...
.
-
A recent study developed growth charts of German MPS III patients. MPS III patients showed an accelerated growth during the 1st year of life but a decelerated growth rate after 4.5 and 5 years for females and males, respectively 2727. Muschol NM, Pape D, Kossow K, et al. Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III). Orphanet J Rare Dis. 2019;14:93. doi:10.1186/s13023-019-1065-x https://doi.org/10.1186/s13023-019-1065-...
.
|
Speech and communication delay |
Expert comments and/or parental concerns
-
Although speech only develops around the age of 12 months, patients with MPS III might already have subtle impairments in communication at a younger age. More in-depth analysis may reveal MPS III-specific communication profiles in infants.
-
Joint attention (the infant’s ability to join the focus of attention of other persons) 3838. Akhtar N and Gernsbacher MA. Joint attention and vocabulary development: a critical look. Lang Linguist Compass. 2007;1(3):195-207. doi:10.1111/j.1749-818X.2007.00014.x https://doi.org/10.1111/j.1749-818X.2007...
and the ability to engage with the environment might initially be better developed in MPS III compared with autism spectrum disorder (personal communication). MPS III patients might initially be more engaged with their parents and the environment and make more eye contact than autism patients. These differences might be helpful in the differential diagnosis.
-
The ability to speak is gradually lost while motor development is preserved longer.
Supporting medical literature
-
Studies demonstrated onset of speech regression at the age of 2.8 years (SD: 1.9) and regression of motor function at 4.1 years (SD: 3.6) for MPS IIIA and similar regression profiles for MPS IIIB 1717. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007;120(5):e1255-e1261. doi:10.1542/peds.2007-0282 https://doi.org/10.1542/peds.2007-0282...
.
-
Speech delay with an initial period of normal motor development might lead to misdiagnosis of an idiopathic speech delay 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169 https://doi.org/10.1111/apa.12169...
,44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
.
|
Behavioral problems |
Expert comments and/or parental concerns
-
Patients with MPS III can have impulsive and fearless behavior. Fearless behavior is difficult to interpret below the age of 2 years. Parents usually only report fearless and impulsive behavior when this becomes abnormal.
-
Hypersensitivity and attention problems frequently occur and can manifest as early as 12-24 months or appear at later ages. MPS III patients typically present autistic-like behavior. Features that might differentiate MPS III from autism are appropriate and functional play, longer attention span and more engagement, fearlessness, less impaired social skills, usually less repetitive or restricted behavior, and no ritualistic behaviors. Children with MPS III also appear to be more aggressive, likely associated with their inability to express themselves due to speech delay and hearing loss.
Supporting medical literature
-
An increased incidence of autistic-like social behaviors occurred between 3-4 years of age in a cohort of children with early-onset MPS IIIA 2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007 https://doi.org/10.1016/j.jpeds.2014.01....
.
-
An increased incidence of behavioral problems emerges between the age of 3 and 4 years and presents as a decrease in engagement with the environment 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189 https://doi.org/10.1186/1750-1172-8-189...
,2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007 https://doi.org/10.1016/j.jpeds.2014.01....
.
-
Hyperactive and fearless behavior that does not respond to standard of care, such as pharmacotherapy for ADHD, differentiating both disorders 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169 https://doi.org/10.1111/apa.12169...
.
|
Hip dysplasia |
Expert comments and/or parental concerns
Supporting medical literatureMusculoskeletal symptoms are less pronounced in MPS III versus other types of MPS, but hip deformities are among the most common orthopedic abnormalities and are related to disease severity 3939. White KK, Karol LA, White DR and Hale S. Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III). J Pediatr Orthop. 2011;31(5):594-598. doi:10.1097/bpo.0b013e31821f5ee9 https://doi.org/10.1097/bpo.0b013e31821f...
,4040. de Ruijter J, Maas M, Janssen A and Wijburg FA. High prevalence of femoral head necrosis in Mucopolysaccharidosis type III (Sanfilippo disease): a national, observational, cross-sectional study. Mol Genet Metab. 2013;109(1):49-53. doi:10.1016/j.ymgme.2013.03.004 https://doi.org/10.1016/j.ymgme.2013.03....
. |
Pain sensation |
Expert comments and/or parental concerns
-
Based on the participants’ experiences, MPS III patients tend to have increased pain tolerance, e.g., MPS III children often do not flinch when blood is drawn or do not feel pain when falling down. However, currently no supporting evidence can be found, and further studies would need to examine if MPS III children experience and/or express pain differently.
|
Mouthing |
Expert comments and/or parental concerns
Supporting medical literatureRestrictive and repetitive behaviors such as hand flapping or rocking are mostly absent while oral restricted behaviors and hyper-orality can be present 2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007 https://doi.org/10.1016/j.jpeds.2014.01....
. |