Published online March 1, 2006
PEDIATRICS
Vol. 117
No. 3
March 2006, pp.
955-958
(doi:10.1542/peds.2005-1032)
Difficulty in Recognizing Multiple Sulfatase Deficiency in an Infant
Roberto P. Santos, MDa and
Joe J. Hoo, MDb
a Department of Pediatrics
b Division of Genetics, Department of Pediatrics, State University of New York-Upstate Medical University, Syracuse, New York
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ABSTRACT
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We describe the difficulty in recognizing multiple sulfatase deficiency (MSD; Online Mendelian Inheritance in Man [OMIM] database No. 272200) in an infant. MSD is a rare autosomal recessive disorder that affects the posttranslational activation of various sulfatase enzymes. It is both biochemically and clinically variable. Currently, there are 12 known sulfatases in humans, and the clinical presentation of MSD is a unique composite of those individual enzyme defects. Here we report a black girl who presented with bilateral broad thumbs and great toes, both with angulation deformities at birth. Rubinstein-Taybi syndrome (OMIM No. 180849) was considered initially. The detection of inclusion bodies in her white blood cells at 37 months of age led to the appropriate diagnostic workups for lysosomal storage diseases. Elevation of urine mucopolysaccharides provided additional clues, and the fibroblast enzyme assays finally established the diagnosis. Broad thumbs and great toes are rare features of MSD, and to the best of our knowledge such a bilateral congenital anomaly with angulation deformities has never been reported before to be associated with MSD.
Key Words: multiple sulfatase deficiency • posttranslational defect • broad and angulated thumbs and great toes
Abbreviations: MSD, multiple sulfatase deficiency • RTS, Rubinstein-Taybi syndrome
Multiple sulfatase deficiency (MSD, Online Mendelian Inheritance in Man database No. 272200) is a very rare autosomal recessive disorder that affects the posttranslational activation of various sulfatase enzymes. Its prevalence is <1 in 1 million births.1 The affected sulfatases have none or reduced catalytic activities to their natural substrates, which leads to an accumulation of complex sulfate esters and eventually to variable clinical phenotypes.1,2 Because multiple enzymes are involved, the clinical presentation of this disorder is a unique admixture of those individual enzyme defects. Generally, the heterogenous clinical presentations may resemble those with late infantile metachromatic leukodystrophy. However, the variable clinical findings depend on which enzyme combinations are deficient among the 12 known sulfatases in humans.2 The exceedingly rare prevalence and the variable biochemical and clinical presentations may pose difficulty in recognizing MSD in an infant. Here we report a black girl who presented with bilateral broad thumbs and great toes, both with angulation deformities noted at birth.
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CLINICAL CASE REPORT
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A black female infant was born at term to a 30-year-old, gravida 2, para 1 mother after an uneventful pregnancy. The family history was unremarkable, and there was no consanguinity. The infant was delivered vaginally with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. Her birth weight was 2963 g (25th percentile), her length was 51.4 cm (75th–90th percentile), and her head circumference was 33.5 cm (50th percentile). At birth she was noted to have bilateral broad thumbs and great toes, both with angulation deformities (Fig 1). Other significant physical findings included mild interdigital skin webbing of the hands and bilateral club feet. There was also short nasal columella but no obvious beaked nose. Aside from diastasis recti, the chest, abdomen, and external genitalia were normal. A skeletal survey done at the second day of life showed the feet in metatarsus varus position with bilateral enlarged great toes. The long bones and the pelvis appeared normal. She was referred to our genetics clinic, and the diagnosis of Rubinstein-Taybi syndrome (RTS) was suspected. However, the other characteristic features of this syndrome were missing, such as microcephaly, beaked nose, and growth retardation. Her karyotype showed 46,XX,inv(9)(p11.2q13); the pericentric inversion of the heterochromatic region of one chromosome 9 was considered to be a normal variant with no known clinical significance.
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FIGURE 1 A, Bilateral broad and angulated thumbs at birth. B, Bilateral broad great toes at birth with club feet deformity. C, Radiograph of both feet at birth. The feet showed medial deviation of enlarged great toes bilaterally.
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She was admitted to the hospital at 7 months of age, initially for severe lower respiratory tract infection. Additional workup showed that she had an increased intracranial pressure in association with hydrocephalus; hence, a ventriculoperitoneal shunt was placed. Her follow-up visit at the genetics clinic at 9 months of age showed a growth failure (both weight and length were <5th percentile) and developmental delay. She had just started to roll over but could not be placed to sit. There was a relative coarsening of facies on top of the previously noted skeletal deformity in her thumbs. At 17 months of age it was noted that her weight and length remained <5th percentile and her head circumference was between the 5th and 10th percentile. An umbilical hernia that measured 2.5 cm in diameter was noted also. No other clinical finding or symptom was apparent. It was thought that the hydrocephalus might have masked the microcephaly of RTS. She was hospitalized again at 31 months of age because of lethargy and decreased appetite. No ventriculoperitoneal shunt malfunction was noted; however, a cranial computed tomography scan showed large ventricles, which were interpreted as being secondary to brain atrophy rather than to a persistent hydrocephalus. Her electroencephalogram showed generalized abnormal slowing without seizure activity. The result of a fluorescence in situ hybridization study for RTS was negative.
Because of feeding problems and continuous weight loss, she underwent fundoplication and gastrostomy-tube placement at 37 months of age. At this admission, the pathology laboratory noted the presence of inclusion bodies in the lymphocytes of her routine complete blood count and blood smear. Because she never received any hyperalimentation, this finding might have suggested a storage disease. Subsequent urine tests for sulfatides and mucopolysaccharides showed elevated glycosaminoglycans (64.8 mg/mol creatine; reference for 1- to 3-year-olds: <11.1 mg/mol). Both dermatan sulfate and heparan sulfate were present, which was consistent with the diagnosis of a mucopolysaccharidosis. Testing of a second batch of urine specimen confirmed the markedly elevated glycosaminoglycans. The urine showed the presence of a large amount of dermatan sulfate and a lesser amount of heparan sulfate, as well as a smaller amount of chondroitin sulfate. A test for urine sulfatide was requested but never performed. Initial enzyme assays on skin fibroblast cells ruled out Hurler disease and Sanfilippo B disease. However, additional enzyme assays at a different reference laboratory revealed deficiencies of 4 sulfatase enzymes (Table 1), which established the diagnosis of MSD.
During an outpatient visit at 40 months of age, she continued to have growth and developmental delay. Her weight and length were way below the 5th percentile, and her head circumference was at the 2nd percentile. She did not sit on her own, and there was no speech at all. She had noisy breathing, foamy saliva, and a distended abdomen. Her gums were hypertrophic, her elbows were relatively stiffened, and the liver edge was palpable 2 cm below her right costal margin. However, her corneas remained clear. Her mother also mentioned the child's dry and occasionally scaly skin, which was treated with topical ointment. Between 43 and 44 months of age, she was admitted several times to the pediatric intensive care unit for aspiration pneumonia, apnea, and worsening respiratory distress. She died shortly after her last admission.
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DISCUSSION
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A population genetic study of lysosomal storage disorder in Australia from 1980 to 1996 revealed that MSD was exceedingly rare. An estimated carrier frequency of close to 1 in 600 was calculated from the prevalence data. The median age at diagnosis was slightly over 8 years, ranging from 7.3 to 8.8 years.1
Difficulty in recognizing or suspecting MSD in infants, because of variations in either clinical or biochemical presentation, has been described previously.3–7 It is difficult to recognize MSD in the newborn period or early infancy, probably because the phenotypic effect of such a metabolic storage disease is not yet fully manifested. If it does show some signs such as the skeletal deformities noted in our patient, they are not distinctly characteristic of MSD. An initial impression of RTS was given for this patient primarily because of the bilateral broad and angulated thumbs and great toes. Although the other distinctive features of RTS such as microcephaly and beaked nose were not present. The initial lack of microcephaly was thought to have been masked by hydrocephaly. The negative fluorescence in situ hybridization study using probe from chromosome region 16p13.3 did not rule out RTS, because only 10% to 25% of patients with RTS are positive for this microdeletion.8 Bilateral broad thumbs with or without bilateral broad great toes have been described before in patients with MSD3,4,7 but without the angulation deformities. The appearance of broad thumbs and great toes cannot be attributed to any of the known sulfatases. Vamos et al9 reported early-onset MSD in a newborn male with clinical and radiologic evidence of multiple bone deformities. These deformities included bilateral club feet, severe hypoplasia of all vertebral bodies, and multiple epiphyseal dysplasia but without bilateral broad thumbs and great toes.
Demonstration of mucopolysaccharides and sulfatides in the urine together with reduced levels of several sulfatases in the leukocyte and/or fibroblast assays confirms the biochemical diagnosis of MSD. The lower the level of sulfatase activity, the more severe the clinical presentation is.10,11 Depending on the onset of the disease, MSD has also been grouped into neonatal, late infantile, and juvenile types. Eto et al12 summarized the clinical and biochemical characteristics of these types of MSD. The mucopolysaccharides (glycosaminoglycans) excretion in patients with MSD had consistently shown an abnormal distribution pattern in different studies, especially those involving dermatan and heparan sulfate fractions.2,5,12 The 4 affected enzymes in our patient include reduced activities of arylsulfatase A and heparin sulfamidase and undetectable activity of N-acetylgalactosamine 6-sulfatase and N-acetylglucosamine 6-sulfatase. Each of the aforementioned enzymes is associated with a distinct disease process: metachromatic leukodystrophy, Sanfilippo syndrome (type A), Morquio syndrome (type A), and Sanfilippo syndrome (type D), respectively.2 Although only fibroblast enzyme assays were performed for our patient, it is prudent to extend the examination to a leukocyte enzyme assay.3–5 Occasionally, steroid sulfatase deficiency may be missed if fibroblast assays alone are done.6 There is no definitive treatment available for MSD at the present time. However, the encouraging prospect of enzyme-replacement therapies is being studied.2
MSD is primarily a defect in the posttranslational modification of sulfatase to its active form. Formylglycine is the key catalytic residue within the active catalytic side of sulfatases, and it is converted from cysteine by the action of formylglycine-generating enzyme (FGE). This enzyme is defective in MSD.13,14 The gene encoding for FGE, known as sulfatase-modifying factor 1 (SUMF1), has been identified and disease-causing mutations have been described. In humans, the gene SUMF1 is located in chromosome 3p26, at the terminal end of the short arm of chromosome 3.15,16 There are at least 12 known sulfatases in humans that act on complex sulfate ester molecules. Hydrolysis of these complex molecules takes place in different cellular locations. Eight of the sulfatases are lysosomal, whereas the other 4 are situated in neutral cellular loci such as the endoplasmic reticulum, Golgi network, and microsomes. The genes for at least 10 of these sulfatases have been isolated. A deficiency in any of these enzymes would lead to storage of their natural substrate molecule, which has toxic effects on cellular function, causing the variable clinical phenotype seen in MSD.2 The 4 known deficient sulfatases in our patient (Table 1) are all located in the lysosomes. The other lysosomal enzymes (ß-galactosidase and 
-iduronidase) were measured in our patient for reference purposes and were noted to be within normal limits.
The significance of early diagnosis is to provide the clinician with a window of opportunity for family counseling.2 This is particularly true in exceedingly rare disorders with no definitive treatment such as MSD. Meikle et al1 showed that there were 2 affected siblings, and in most cases both were born before the first was diagnosed with lysosomal storage disease. Families of patients with MSD should be counseled accordingly, because prenatal diagnosis is available. It has been reported that MSD is one of the disorders affecting the fetus that is associated with low estriol during pregnancy.17 Demonstration of decreased arylsulfatase and sulfamidase activities from direct assays of chorionic villi allows a first-trimester diagnosis.18 Levels of various sulfatase activities from cultured amniotic cells after amniocentesis may be used in second-trimester prenatal diagnosis2 or by determination of oligosaccharides and glycolipids in amniotic fluid.19
This case illustrates the difficulty in recognizing an infant with MSD. A high index of suspicion could lead to the correct diagnostic workup despite its variable biochemical and clinical presentations. Elevation of urine mucopolysaccharides and sulfatides provided additional clues, and the fibroblast and/or leukocyte enzyme assays finally established the correct diagnosis.
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ACKNOWLEDGMENTS
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We are indebted to Robert Hingre, MD, and Patricia Mondore for constructive and critical comments.
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FOOTNOTES
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Accepted Jul 21, 2005.
Address correspondence to Roberto P. Santos, MD, Department of Pediatrics, Division of Infectious Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9063. E-mail: roberto.santos{at}utsouthwestern.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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ABSTRACT
CLINICAL CASE REPORT
