Multiple sulfatase deficiency (ORPHA:585)
A rare lysosomal disease characterized by a clinical phenotype that combines the features of different sulfatase deficiencies (whether lysosomal or not). Clinical manifestations can include developmental delay, progressive neurologic deterioration, hydrocephalus, hypotonia, coarse facial features, retinopathy, skeletal anomalies, hepatomegaly and ichthyosis to a variable degree. Multiple sulfatase deficiency (MSD) comprises severe to attenuated forms historically classified as neonatal (most severe form), infantile (most common form) or juvenile (rarest form).
Epidemiology
The estimated prevalence is 1/500,000. So far, there are approximately 150 reported cases without apparent ethnological and sexual distribution.
Clinical description
This disease begins between birth and the juvenile period. Patients with an early neonatal form can present with intrauterine growth retardation and respiratory distress at birth. They may also have facial dysmorphism, skeletal abnormalities, splenomegaly, congenital heart defects, ichthyosis and muscle hypotonia. Failure to thrive is a common clinical sign inherent to the different clinical MSD presentations. The infantile form often presents with developmental delay preventing the child from reaching developmental milestones, mildly coarse facial features, ichthyosis, organomegaly, dysostosis multiplex, and ichthyosis of variable degree. Attenuated forms differ from severe forms in that the disease progresses more slowly and not all clinical signs need to be present. Patients often achieve independent ambulation and speech before neurocognitive decline begins. Retinopathy, gallbladder sludge, hydrocephalus, hypertrichosis, dysostosis multiplex, and neuropathy can occur at all stages and in every form of MSD.
Etiology
An autosomal recessive mutation in the SUMF1 gene on chromosome 3p26 causes MSD. The mutation alters the function of the sulfatase-activating enzyme FGE (Formylglycine-generating enzyme). There exist over 50 pathogenic mutations of SUMF1 most of which are missense mutations allowing residual FGE function towards sulfatase activation that result in reduced (to a variable degree) or completely absent activity sulfatases (lysosomal or not).
Diagnostic methods
Clinical manifestations associated with a detection of glycosaminoglycans and sulfatides in the urine is indicative of MSD. The diagnosis is confirmed if there is loss of activity of at least two sulfatases in leukocytes or if a genetic test reveals a pathogenic mutation in the SUMF1 gene.
Differential diagnosis
Differential diagnosis includes all single sulfatase deficiencies like metachromatic leukodystrophy (arylsulfatase A deficiency), Hunter syndrome, Maroteaux-Lamy syndrome, or Sanfilippo syndrome type A and D among others. X-linked ichthyosis, saposin B deficiency, mucolipidosis and other lysosomal diseases are additional differential diagnosis.
Antenatal diagnosis
Preimplantation and prenatal genetic testing can be performed if pathogenic SUMF1 variants have been identified in an affected family member.
Genetic counseling
The transmission is autosomal recessive. With each pregnancy, there is a 25% chance that the child will be affected and a 50% chance that the child will be a carrier.
Management and treatment
Currently, no specific treatment exists. A multidisciplinary approach is essential to increase quality of life and includes physiotherapy, skin treatment, neurological examinations, and monitoring of bone fragility, hearing, vision, gastrointestinal and respiratory disorders.
Prognosis
MSD has multiple clinical expressions and a prognosis can be hard to establish. However there exist different categories of MSD which may help evaluate its severity. The 50% survival rate has been estimated to be approximately 13 years. High motor function, achievement of speech, low number of clinical signs at a given age and high residual functionality of the FGE variant correlate with an attenuated course of MSD, and vice versa.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Dr Laura ADANG  - Dr Rebecca AHRENS-NICKLAS  - Dr Lars SCHLOTAWA