A Rare Case of Late Infantile Form of Multiple Sulfatase Deficiency

Dear Editor, A two-year-old girl child, referred to us by a pediatrician, and born to a healthy non-consanguineous couple, presented with complaints of dry skin lesions over legs, arms, and trunk for 6–7 months. She also had history of not being able to sit and stand for 3 months. The pregnancy was uneventful with full-term vaginal delivery and birth weight of 3 kg. There was no history of similar presentation in family. She had neither previous developmental delays nor serious infections. Before the presentation of the disease, medical evaluations were normal, with no neurological impairments and no abnormalities in tendon reflexes. On cutaneous examination, she had ichthyosis over bilateral upper limb, abdomen, and bilateral lower limb [Figures 1-3]. On ophthalmologic evaluation, she had strabismus, avoided eye contact, slit lamp examination showed bilateral corneal haziness, and fundus examination was normal. As the ophthalmological examination turned out to be normal, it was not in favor of Sjögren–Larsson syndrome so patient was further investigated for neurological involvement. On neurological evaluation, her head control was absent and had global hypertonia. She also had upper and lower tendon hyperreflexia of +3 grade (bilateral lower limb more than bilateral upper limb) and bilateral upward Babinski sign.Figure 1: Ichthyosis over bilateral upper limbFigure 2: Ichthyosis over abdomenFigure 3: Ichthyosis over bilateral lower limbPatient's complete blood count was within normal limits. Details of relevant investigations are summarized in Table 1. For proper molecular diagnosis, the patient was advised to undergo genetic analysis using whole exome gene sequencing, and final diagnosis of multiple sulfatase deficiency was confirmed. However, Sanger sequencing of the patient and parents was not done due to financial constraints. Anticipatory guidance was given to her parents about the disease, but unfortunately after a month, patient succumbed to death.Table 1: Details of relevant laboratory and radiological investigations at presentationMultiple sulfatase deficiency (MSD) is a type of lysosomal storage disorder (LSD) caused by homozygous or compound heterozygous mutation in the sulfatase-modifying factor 1 (SUMF1) gene. MSD is an inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy and of various mucopolysaccharidoses. Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Several different clinical subtypes of MSD have been described[1]: Neonatal MSD is the most severe type with presentation in the prenatal period or at birth with rapid progression and death occurring within the first two years of life. Infantile MSD is the most common variant and may be characterized as attenuated (slower clinical course with cognitive disability and neurodegeneration identified in the 2nd year of life) or severe (loss of the majority of developmental milestones by age 5 years). Juvenile MSD is the rarest subtype with later onset of symptoms and subacute clinical presentation. Genetically, more than 30 different mutations in the SUMF1 gene, which is located on chromosome 3p26.1, have been discovered. SUMF1 encodes formyl glycine-generating enzyme (FGE), which is essential for the post-translational activation of all sulfatases in the endoplasmic reticulum. The severity of FGE protein instability and residual catalytic ability influences the clinical severity and phenotype of MSD. Severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the milder forms are due to mutations that lead to reduced level of normally functioning FGE. The wide clinical spectrum seen in MSD is largely a function of the unique pathophysiology of this condition, as multiple pathways are affected by a common enzymatic defect. Out of the 17 known human sulfatases, nine are individually implicated in single sulfatase deficiency diseases.[2] The clinical presentation of multiple sulfatase deficiency is therefore heterogeneous and attributed to the overarching features of the nine defined single sulfatase deficiencies.[3] Systemic sequelae of MSD are vast and multisystemic, primarily encompassing developmental delay and neurological, cardiopulmonary, dermatological, gastroenterological, and skeletal manifestations. The systemic features of multiple sulfatase deficiency overarchs with various types of LSD [Table 2].[4]Table 2: Cutaneous and systemic manifestations in various genodermatoses associated with spasticity and ichthyosisOver and above Sjögren–Larsson syndrome, spasticity with ichthyosis is also seen in other genodermatoses [Table 2], so they should be ruled out as well. However, in this case, our expectations were supplanted by several findings that helped us reach the final diagnosis. While there are no targeted therapeutic options to date, many complications are amenable to symptomatic management. However, patients should avoid neck hyperextension, including hyperextension used for intubation because of the risk of spinal cord compression and foods that are choking hazards should also be avoided. It is important to consider the possibility of MSD in a child with skin problems and neurological deterioration. Detailed skin, physical, and neurological examination is mandatory in a dermatology clinic in a patient with either metachromatic leukodystrophy or mucopolysaccharide deficiency to rule out various genodermatoses with spasticity and ichthyosis. Molecular genetic analysis should be performed in all cases to elucidate the disease causing mutation as a prerequisite for precise genetic counselling and prenatal molecular genetic diagnosis. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.