In MPS III A the deficiency of heparan N-sulfatase results in lysosomal accumulation of undegraded heparan sulphate and eventually in progressive cellular destruction and multisystemic disease [1],[2].
Despite biochemical differences, subtypes of MPS III are virtually indistinguishable for clinicians. However, there are data suggesting that the clinical course of MPS IIIA is more severe, with an earlier onset, more rapid progression of symptoms and shorter survival than the other subtypes [1].
The majority of children with MPS IIIA were born after uneventful pregnancies [1],[3]. Buhrman et al. found that the most common pregnancy complication was caesarean section due to failure to progress, macrocephaly and breech position, suggesting that the GAGs storage already occur before birth, which was also found in our patient’s perinatal history [4].
Interestingly, Meyer et al. noticed a high number of miscarriages in mothers of children with MPS IIIA (29%). The above data need to be interpreted with caution as the incidence of miscarriages is age-dependent and the exact age of mothers at the time of miscarriage was unknown. However, further research should be performed to investigate the risk of miscarriage in pregnancies involving children with MPS [3].
In general, the early development of a child with MPS IIIA is normal. Nevertheless, the latest studies of the natural course of MPS IIIA showed that the initial symptoms of the disease were present in many patients already during the first year of life [3],[4]. Furthermore, Meyer et al. found that three quarters of children with MPS IIIA did not achieve normal early developmental milestones. In 40.6% of children a delay of speech development (late talking >15 months) was observed, while only in 7.2 % delay in motor development (late walking >18 months). In 26.1% of children delay in both speech and motor development was noticed [3]. However, the median age at MPS IIIA diagnosis varied from 3 – 4.5 years [3],[4].
Meyer et al. shown that the first symptoms observed by parents in children with MPS were behavioural problems and sleep disturbances [3]. These findings differ from those of Buhrman et al. who found that the most common initial symptom was speech delay (48%), while abnormal behaviours were observed in 9% of patients [4]. In our patient the first symptoms which alarmed his parents were psychomotor progressive retardation and behavioural problems including restlessness, hyperactivity and impulsivity. Sleep disturbances were not observed in our patient.
Severe behavioural and sleep problems are well-established symptoms of Sanfilippo syndrome. The reported behavioural problems include restlessness, severe hyperactivity, impulsivity, temper tantrums, aggression, unusual affect, i.e. laughing or crying fits [2],[5]. Sleep disturbances are one of the major concerns in patients with Sanfilippo syndrome, affecting 72 to 96% of patients. The most common sleep problems include settling difficulties, early waking, nocturnal waking, and night-time behaviours like chewing bedclothes, crying, singing or laughing in the night. Some patients show no circadian rhythm [5].
Somatic symptoms in Sanfilippo syndrome are less overt than in the other types of MPS. However, there is a growing body of evidence confirming significant somatic manifestation of MPS IIIA, including coarse facial features, hepatomegaly, hernia, heart disease, hearing impairment, recurrent airway infections, persisting diarrhoea, epilepsy and skeletal abnormalities [3],[4],[6]. In our patient facial dysmorphism (coarse facial features, the slightly depressed nasal bridge, prominent eyebrows, low set ears, malocclusion, full cheeks, wiry and dry hair and the short neck) and skeletal symptoms (excessive lumbosacral lordosis, genu valga, and varus feet) were evident.
In a child with skeletal abnormality imaging findings may provide a key diagnostic clue. The group of radiological symptoms in mucopolysaccharidosis is known as dysostosis multiplex and include abnormally shaped vertebrae and ribs, enlarged skull, spatulate ribs, hypoplastic epiphyses, thickened diaphyses and bullet-shaped metacarpals. The other common skeletal symptoms are thoracolumbar kyphosis and gibbus deformity, hip dysplasia and genu valgum [7]. Skeletal abnormalities in Sanfilippo syndrome are less prominent than in the other types of MPS and tend to appear after neurocognitive manifestations [4],[7]. However, regular imaging of the vertebral column, hips and lower extremities is recommended for patients with MPS [7]. Unfortunately, there is no available X-ray of our patient’s skeletal system.
It should be highlighted that lack of somatic symptoms including facial dysmorphism, should not exclude the diagnosis of MPS IIIA [2]. Large variability in the clinical spectrum of MPS may be a result of residual enzyme activity caused by different gene mutations [3]. However, genotype-phenotype correlations remain unclear and need further investigations [6].
The best to our knowledge chronic hepatitis is not the established symptom of MPS IIIA. Based on detailed diagnostic work-up in our patient, we excluded many possible causes of chronic hypertransaminasemia i.e. infectious hepatitis, muscular dystrophy, autoimmune hepatitis, α1-antitrypsin deficiency, lysosomal acid lipase deficiency, and Wilson’s disease. Chronic hypertransaminasemia and the bright liver on ultrasound in our patient may suggest non-alcoholic steatohepatitis (NASH). It may be also related to the liver storage of glycosaminoglycans. However, such an explanation tends to overlook the fact that in another mucopolysaccharidosis – Hunter syndrome (MPS II) – the storage of glycosaminoglycans in the liver does not lead to its dysfunction [8]. Unfortunately, to date no research has been focused on the problem of liver injury in Sanfilippo syndrome. Nevertheless, liver biopsy is required for definitive diagnosis. Thus, we referred the child to the Paediatric Metabolic Diseases and Gastrohepatology Outpatient Clinic, The Children’s Memorial Health Institute in Warsaw, for further diagnostic evaluation and treatment.
The present case underlines the importance of holistic approach to paediatric patient based on thorough medical history and physical examination. It should be noted that early clinical suspicion is crucial to establish the diagnosis.