Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C &gt; A; p.S64X and c.818A &gt; G; p.D273G)

Ballabio, A.

Bernasconi, S.

Braibanti, S.

Frattini, D.

Gabrielli, O.

Galeazzi, T.

Garavelli, L.

Gargano, G.

Gelmini, C.

Iori, A.

Iughetti, L.

Ivanovski, I.

Melli, N.

Padella, L.

Pedori, S.

Pepe, S.

Rosato, S.

Santoro, L.

Superti-Furga, A.

Wischmeijer, A.

Zampini, L.

The Italian Journal of Pediatrics

PubMed

Serveur académique lausannois

ITALIAN JOURNALOF PEDIATRICSGaravelli et al. Italian Journal of Pediatrics  (2014) 40:86 DOI 10.1186/s13052-014-0086-2CASE REPORT Open AccessMultiple sulfatase deficiency with neonatalmanifestationLivia Garavelli1*, Lucia Santoro2, Alexandra Iori1,3, Giancarlo Gargano4, Silvia Braibanti4, Simona Pedori4, Nives Melli4,Daniele Frattini5, Lucia Zampini2, Tiziana Galeazzi2, Lucia Padella2, Stefano Pepe6, Anita Wischmeijer1,7, Simonetta Rosato1,Ivan Ivanovski1, Lorenzo Iughetti3, Chiara Gelmini1, Sergio Bernasconi8, Andrea Superti-Furga9, Andrea Ballabio6,10,11,12and Orazio Gabrielli2AbstractMultiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism causedby mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), andresulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Lessthan 50 cases have been published so far. We report a new case of MSD presenting in the newborn period withhypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compoundheterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G).Keywords: Multiple sulfatase deficiency, MSD, SUMF1 geneIntroductionMultiple Sulfatase Deficiency is a rare autosomal reces-sive inborn error of metabolism characterized by thedefective activity of all known sulfatases [1]. It is caused bymutations in the sulfatases- modifying factor 1 geneencoding the FGE. Sulfatases are a family of enzymes thatcatalyze the hydrolysis of ester sulfates, including glycos-aminoglycans, sulfolipids and steroid sulfates. These pro-teins share high amino acid sequence homology. Howeverthey show different sub-cellular localization and substratespecificity [1,2]. The SUMF1 gene encodes for a sulfatase-modifyng factor, which converts a highly conserved cysteinewithin the sulfatase catalytic domain into Cα- formylglycine[3]. It has been shown that this post-translational modi-fication is both an essential and limiting factor for theenzymatic activity of sulfatases [4]. The SUMF1 gene islocated on chromosome 3p26. It spans 105 kb and thecoding sequence is distributed over 9 exons. The cDNA forhuman FGE is predicted to encode a protein of 374 resi-dues. The protein contains a cleavable signal sequenceof 33 residues, which indicates translocation of FGE* Correspondence: garavelli.livia@asmn.re.it1Clinical Genetics Unit, Obstetric and Pediatric Department, Istituto diRicovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova,Reggio Emilia, ItalyFull list of author information is available at the end of the article© 2014 Garavelli et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.into the endoplasmatic reticulum, and contains a singleN-glycosylation site at Asn-141 [5]. The middle part ofFGE (residues 179–308 in human FGE) is represented bya tryptophan-rich subdomain. The C-terminal subdomain(residues 327–366 in human FGE) is the most highlyconserved sequence within the FGE family.FGE post translationally activates all newly synthesizedsulfatase by generating the catalytic residue formylgly-cine. Impaired FGE function leads to a reduction insulfatase activities. It has been proved that variability ofthe clinical phenotype depends on both residual FGE ac-tivity as well as protein stability [6]. MSD is characterizedby features of mucoplysaccharidosis and metachromaticleukodystrophy including neurologic deterioration anddevelopment delay, gargoyle-like features, visceromegaly,heart involvement, ichthyosis, hydrocephaly, cloudycorneal and skeletal anomalies [7]. According to the age ofonset, very neonatal, late infantile (severe or LIS and mildor LIM) and rare juvenile (mild) disease subtypes can bedistinguished [8].We described a clinical case of a girl with a neonatalform of MSD, presenting typical findings of the disease.She was compound heterozygous for two so far undescribedSUMF1 mutations (c.191C >A; p.S64X and c.818A > G;p.D273G).l. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 2 of 4Clinical reportThe girl is the first child of healthy, non-consanguineousparents. She was born by vaginal delivery at week 40 withbirth weight of 2,815 g, length 46 cm, and head circumfer-ence 32 cm. APGAR scores were 9/10. At 20 hours of lifeshe was transferred to our Neonatal Intensive Unit be-cause of the appearance of rolling eyes followed byepisodes of apnoea with cyanosis and hypotonia, for whicha treatment with phenobarbital was installed. At that time,physical examination showed coarse facial features, high-arched, thick eyebrows, bulbous nasal tip, micrognathia,posteriorly rotated ears with attached lobes, flared thorax,inverted nipples, hepatosplenomegaly, broad thumbs, mildichthyosis and muscular hypotonia. (Figure 1A, B, C, D).At 11 days of life she presented two episodes of obstruct-ive respiratory arrest after stridor, treated with ventilation.The otolaryngologist’s evaluation revealed the presence ofa cystic formation of the vallecula, which was removedsurgically with resolution of the episodes of apnoea.Because of the coarse facial features, hypertrichosis,and hepatosplenomegaly, a lysosomal storage disorderFigure 1 Phenotype. A: coarse face, high-arched, thick eyebrows,bulbous nasal tip and mild ichthyosis. B: micrognathia, posteriorly rotatedears with attached lobes. C: abdominal ichthyosis. D: ichthyosis of thelower limb and feet.was considered. There was an increased urinary excretionof glycosaminoglycans (1101 μg/mg creatinine; normalrange, 30–200), with chondroitin sulfate (+++), dermatansulfate (+++) and heparan sulfate (++) on electrophoresis.Enzyme activitiy testing in leucocytes showed deficiencyof arylsulfatase A (0.0 nM/mg/h; n.v. 40–270), arylsulfa-tase B (0.0 nM/mg/h; n.v. 70–126), iduronate sulfatase(0.9 nM/mg/4 h; n.v. 51–123) and galactose 6 sulfatase(0.6 nM/mg/17 h; n.v.20-27). This pattern was diagnosticof Multiple sulfatase deficiency (MSD). Molecular analysisof the gene SUMF1 revealed two so far undescribedheterozygous mutations: c.191C > A s. S64X in exon 1and c.818A >G p.D273G in exon 6. The first heterozygousmutation was also demonstrated in the girl’s mother, whilethe second one was identified in the girl’s father.The karyotype was normal, 46,XX. The echocardiographyand EEG were normal; abdominal ultrasound showedhepatomegaly; brain magnetic resonance imaging (MRI)showed dilated lateral ventricles with an enlarged cisternamagna, demyelination of the white matter, partial corpuscallosum hypoplasia with hypothrophy of the spleniumand dismorphism of the hippocampum. Skeletal radio-graphy revealed a pattern of dysostosis multiplex withhypoplasia of L2, lumbar kyphosis and platyspondyly ofthe cervical vertebral bodies; broad ribs; broad and hypo-plastic first metacarpals, pointing of the second andthird metacarpals, irregularity of the distal radial andulnar metaphysis (Figure 2A, B, C, D). The ABR examin-ation showed mild hypoacusia.The child presented global developmental delay: couldhold head up only at the age of 10 months, at the age of12 months she was still hypotonic, with limited andjerky movements and it was impossible to meet her gaze.She developed dorso-lumbar kyphosis and owing to L2hypoplasia she had to wear a orthopaedic corset.She was seen again in our Clinical Genetics Unit at24 months of age. Her head circumference was 45 cm(50th centile), length 66 cm (<3rd centile), and weight6.406 Kg (<<3rd centile). Her psychomotor developmentwas severely delayed and she uttered no words. At theage of 24 months she could not sit up unaided.DiscussionMultiple sulfatase deficiency is a rare autosomal recessiveinborn error of metabolism affecting post-translational ac-tivation of sulfatases by the formylglycine generating en-zyme (FGE). Due to mutations in the encoding SUMF1gene, FGE’s catalytic capacity is impaired, resulting inreduced cellular sulfatase activities [9]. More than 30different SUMF1 mutations are known, most of them mis-sense mutations that affect stability and residual molecularactivity of mutant FGE, which both determine MSDdisease severity [10]. A variable residual activity of thedifferent sulfatases has been described [1,11].Figure 2 X-Rays. A: broad and hypoplastic first metacarpals, pointing of the second and third metacarpals, irregularity of the distal radial andulnar metaphysis. B: platyspondily of the cervical vertebral bodies. C: hypoplastic vertebral body of L2, lumbar kyphosis. D: broad ribs.Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 3 of 4Few studies were able to show a correlation of bothresidual activity and stability of FGE variants with theclinical presentation of selected MSD patients. Patients withdrastic impairments of both FGE stability and residualenzyme activity displayed the most severe clinical pheno-type whereas the mildest phenotype was associated with thehighest residual FGE activity among the studied variants.It is now possible to establish a genotype/phenotypecorrelation for MSD and to roughly predict the clinicalcourse for patients with the studied SUMF1 mutations.Missense mutations affecting crucial functional or struc-tural residues in FGE, as well as nonsense ones, will causesevere forms of the disease, whereas missense mutationsnot fully abrogating a functional conformation of the FGEprotein will lead to attenuated forms [6].Different types of MSD can be distinguished accordingto the age of onset: neonatal, late infantile (0 to 2 years,severe or LIS and mild or LIM), and rare juvenile (2 to4 years, mild) [8].The clinical picture of MSD combines symptoms ofthe different sulfatase deficiencies. Patients show neuro-logical deterioration and a neurodegenerative course ofdisease similar to metachromatic leukodystrophy. Develop-ment delay, dysmorphism and organomegaly are presentas found in various mucopolysaccharidoses [6]. Skeletalabnormalities remind one of Chondrodysplasia punctatatype 1 and skin changes of X-linked ichthyosis [1].The onset of symptoms in early infancy is associatedwith poor chances of survival; conversely, when featuresof the disease appear in late infancy, patients survivelonger.In general it is rare to carry out a diagnosis of storagedisease in newborns apart from I-cell disease also knownas mucolipidosis II, which is a condition with a severeclinical course, typical radiological aspects and fibroblastinclusions. Other symptoms include hyperplastic gums,thoracic deformities and congenital hip dislocation whichare evident in newborn age. In the other storage diseasesthe symptoms are not so evident in the newborn age.The diagnosis of MSD may not be simple due to therarity of the condition: in our case the features which ledus to suspect the diagnosis were the MPS-like phenotype,the radiological signs compatible with “dysostosis multi-plex” and especially the cutaneous features. The child hadno signs of chondrodysplasia punctata, in particular noepiphyseal stippling.Indeed the presence of ichthyosis can be a very usefulindicator in identifying the condition and can be the bestmarker of the disease in newborns.Our patient had typical features of neonatal MSD in-cluding neonatal hypotonia, coarse face, mild deafness,visceromegaly, hypoplastic vertebral bodies and delayedpsychomotor development.It was demonstrated that the phenotypic outcome de-pends on both residual FGE activity as well as proteinstability [6]. Another neonatal case was described whichshowed all the clinical symptoms of the condition and aquick worsening course of the disease: he presented twononsense mutations leading to almost fully abrogatedFGE activity, highly unstable FGE protein and nearlyundetectable sulfatase activity [6]. Our case presents amissense mutation along with a nonsense mutation.In fact we have identified two so far undescribed SUMF1mutations (c.191C >A; p.S64X and c.818A >G; p.D273G),resulting in a severe clinical phenotype with early onset,but which allow survival beyond one year of life, in con-trast with what has been reported in literature up to thispoint. She has a serious clinical aspect, but probably lessGaravelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 4 of 4severe than that described by Schlotawa and is still alive atthe age of 2 years.MSD is still an untreatable disease. Thus, potentialtreatment approaches, and also genetic counselling,directly depend on thorough analyses of the functionalconsequences of human SUMF1 mutations on the clinicaland biochemical phenotype.Understanding better the molecular mechanism at theroot of this condition could aid the identification of themost appropriate therapeutic approach of MSD in thenear future.ConclusionIn conclusion, our patient illustrates well the main clinicalfeatures to suspect this condition in the newborn age,ichthyosis in particular, the wide spectrum of clinicalmanifestations and biochemical abnormalities of this raredisease. This case serves to highlight the importance offull and detailed evaluation of all patients with rare dis-orders and the need for continued updates of suggestedsurveillance for these diseases.ConsentWritten informed consent was obtained from the patient’sguardian/parent/next of kin for the publication of thisreport and any accompanying images”.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsLG and AI wrote the manuscript, LG, LS, GG, SB, NM, DF, LZ, TG, LP, AW,SR, II, LI, CG, SB, AS-F and OG participated in the diagnostic process, AS-Fevaluated the X-Rays, SP and AB carried out the molecular genetic tests.All authors read and approved the final manuscript.AcknowledgementsThe authors wish to thank the co-operating family-members for the necessarymedical data and photographs for publication as well as the photographersMarco Bonazzi and Luca Valcavi. This research was funded in part byFondazione Manodori.Author details1Clinical Genetics Unit, Obstetric and Pediatric Department, Istituto diRicovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova,Reggio Emilia, Italy. 2Pediatrics Unit, UNIVPM, Ancona, Italy. 3Department ofMedical and Surgical Sciences of Childhood and Adult, University of Modenaand Reggio Emilia, Modena, Italy. 4Neonatal Intensive Care Unit, Obstetricand Pediatric Department, Istituto di Ricovero e Cura a Carattere Scientifico,Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. 5Pediatric NeurologyUnit, Obstetric and Pediatric Department, Istituto di Ricovero e Cura aCarattere Scientifico, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.6Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino111, 80131 Naples, Italy. 7Department of Medical Genetics, PoliclinicoSant’Orsola-Malpighi, University of Bologna, Bologna, Italy. 8Deparment ofPediatrics, University of Parma, Parma, Italy. 9Department of Pediatrics, CentreHospitalier Universitaire Vaudois, University of Lausanne, Lausanne,Switzerland. 10Department of Molecular and Human Genetics, Baylor Collegeof Medicine, Houston, TX 77030, USA. 11Jan and Dan Duncan NeurologicalResearch Institute, Texas Children Hospital, Houston, TX 77030, USA.12Medical Genetics, Department of Translational Medicine, Federico IIUniversity, Via Pansini 5, 80131 Naples, Italy.Received: 11 August 2014 Accepted: 28 October 2014References1. Hopwood J, Ballabio A: Multiple sulfatases deficiency and the nature ofthe sulfatase family. In The metabolic and molecular bases of inheriteddisease. Edited by Mac Graw Hill. New York: Scriver CR; 2001:3725–3732.2. Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson CP Jr:Regulation of Wnt signaling and embryo patterning by an extracellularsulfatase. Science 2001, 293:1663–1666.3. Schmidt B, Selmer T, Ingendoh A, Von Figura K: A novel amino acidmodification in sulfatase that is defective in multiple sulfatasedeficiency. Cell 1995, 82(2):271–278.4. Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G,Ballabio A: The multiple sulfatase deficiency gene encodes an essentialand limiting factor for the activity of sulfatases. Cell 2003, 113(4):445–456.5. Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M,von Figura K: Multiple sulfatase deficiency is caused by mutations inthe gene encoding the human C(alpha)-Formylglycine generatingenzyme. Cell 2003, 113(4):435–444.6. Schlotawa L, Ennemann EC, Rahakrishnan K, Schmidt B, Chakrapani A,Christen H-J, Moser H, Steinmann B, Dierks T, Gartner J: SUMF1 mutationsaffecting stability and activity of formylglycine generating enzymepredict clinical outcome in multiple sulfatase deficiency. Eur J HumGenet 2011, 19:253–261.7. Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R,Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GMS,Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M,Ballabio A: Molecular and functional analysis of SUMF1 mutations inmultiple sulfatase deficiency. Hum Mutat 2004, 23:576–581.8. Eto Y, Gomibuchi I, Umezawa F, Tsuda T: Pathochemistry, pathogenesisand enzyme replacement in multiple sulfatase deficiency. Enzyme 1987,38:273–279.9. Schlotawa L, Radhakrishnan K, Baumgartner M, Schmid R, Schmidt B, Dierks T,Gartner J: Rapid degradation of an active formylglycine generating enzymevariant leads to a late infantile severe form of multiple sulfatase deficiency.Eur J Hum Genet 2013, 21(9):1020–1023.10. Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gartner J: Molecularanalysis of SUMF1 mutations: stability and residual activity of mutantformylglycine-generating enzyme determine disease severity in multiplesulfatase deficiency. Hum Mutat 2008, 29:205.11. Blanco-Aguirre ME, Kofman-Alfaro SH, Rivera-Vega MR, Medina C, Valdes-Flores M,Rizzo WB, Cuevas-Covarrubias SA: Unusual clinical presentation in two casesof multiple sulfatases deficiency. Pediatr Dermatol 2001, 18(5):388–392.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Multiple sulfatase deficiency with neonatal manifestation.

Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formyglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C¿>¿A; p.S64X and c.818A¿>¿G; p.D273G)

Garavelli, L

Santoro, L

Iori, A

Gargano, G

Braibanti, S

Pedori, S

Melli, N

Frattini, D

Zampini, L

Galeazzi, T

Padella, L

Pepe, S

Wischmeijer, A

Rosato, S

Ivanovski, I

Gelmini, C

Bernasconi, S

Superti Furga, A

Ballabio, A

IUGHETTI, Lorenzo

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Livia Garavelli

Lucia Santoro

Alexandra Iori

Giancarlo Gargano

Silvia Braibanti

Simona Pedori

Nives Melli

Daniele Frattini

Lucia Zampini

Tiziana Galeazzi

Lucia Padella

Stefano Pepe

Anita Wischmeijer

Simonetta Rosato

Ivan Ivanovski

Lorenzo Iughetti

Chiara Gelmini

Sergio Bernasconi

Andrea Superti-Furga

Andrea Ballabio

Orazio Gabrielli

Springer - Publisher Connector

ITALIAN JOURNAL
OF PEDIATRICS
Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 
DOI 10.1186/s13052-014-0086-2CASE REPORT Open AccessMultiple sulfatase deficiency with neonatal
manifestation
Livia Garavelli1*, Lucia Santoro2, Alexandra Iori1,3, Giancarlo Gargano4, Silvia Braibanti4, Simona Pedori4, Nives Melli4,
Daniele Frattini5, Lucia Zampini2, Tiziana Galeazzi2, Lucia Padella2, Stefano Pepe6, Anita Wischmeijer1,7, Simonetta Rosato1,
Ivan Ivanovski1, Lorenzo Iughetti3, Chiara Gelmini1, Sergio Bernasconi8, Andrea Superti-Furga9, Andrea Ballabio6,10,11,12
and Orazio Gabrielli2Abstract
Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused
by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and
resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less
than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with
hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound
heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G).
Keywords: Multiple sulfatase deficiency, MSD, SUMF1 geneIntroduction
Multiple Sulfatase Deficiency is a rare autosomal reces-
sive inborn error of metabolism characterized by the
defective activity of all known sulfatases [1]. It is caused by
mutations in the sulfatases- modifying factor 1 gene
encoding the FGE. Sulfatases are a family of enzymes that
catalyze the hydrolysis of ester sulfates, including glycos-
aminoglycans, sulfolipids and steroid sulfates. These pro-
teins share high amino acid sequence homology. However
they show different sub-cellular localization and substrate
specificity [1,2]. The SUMF1 gene encodes for a sulfatase-
modifyng factor, which converts a highly conserved cysteine
within the sulfatase catalytic domain into Cα- formylglycine
[3]. It has been shown that this post-translational modi-
fication is both an essential and limiting factor for the
enzymatic activity of sulfatases [4]. The SUMF1 gene is
located on chromosome 3p26. It spans 105 kb and the
coding sequence is distributed over 9 exons. The cDNA for
human FGE is predicted to encode a protein of 374 resi-
dues. The protein contains a cleavable signal sequence
of 33 residues, which indicates translocation of FGE* Correspondence: garavelli.livia@asmn.re.it
1Clinical Genetics Unit, Obstetric and Pediatric Department, Istituto di
Ricovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova,
Reggio Emilia, Italy
Full list of author information is available at the end of the article
© 2014 Garavelli et al.; licensee BioMed Centra
Commons Attribution License (http://creativec
reproduction in any medium, provided the or
Dedication waiver (http://creativecommons.or
unless otherwise stated.into the endoplasmatic reticulum, and contains a single
N-glycosylation site at Asn-141 [5]. The middle part of
FGE (residues 179–308 in human FGE) is represented by
a tryptophan-rich subdomain. The C-terminal subdomain
(residues 327–366 in human FGE) is the most highly
conserved sequence within the FGE family.
FGE post translationally activates all newly synthesized
sulfatase by generating the catalytic residue formylgly-
cine. Impaired FGE function leads to a reduction in
sulfatase activities. It has been proved that variability of
the clinical phenotype depends on both residual FGE ac-
tivity as well as protein stability [6]. MSD is characterized
by features of mucoplysaccharidosis and metachromatic
leukodystrophy including neurologic deterioration and
development delay, gargoyle-like features, visceromegaly,
heart involvement, ichthyosis, hydrocephaly, cloudy
corneal and skeletal anomalies [7]. According to the age of
onset, very neonatal, late infantile (severe or LIS and mild
or LIM) and rare juvenile (mild) disease subtypes can be
distinguished [8].
We described a clinical case of a girl with a neonatal
form of MSD, presenting typical findings of the disease.
She was compound heterozygous for two so far undescribed
SUMF1 mutations (c.191C >A; p.S64X and c.818A > G;
p.D273G).l. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
iginal work is properly credited. The Creative Commons Public Domain
g/publicdomain/zero/1.0/) applies to the data made available in this article,
Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 2 of 4Clinical report
The girl is the first child of healthy, non-consanguineous
parents. She was born by vaginal delivery at week 40 with
birth weight of 2,815 g, length 46 cm, and head circumfer-
ence 32 cm. APGAR scores were 9/10. At 20 hours of life
she was transferred to our Neonatal Intensive Unit be-
cause of the appearance of rolling eyes followed by
episodes of apnoea with cyanosis and hypotonia, for which
a treatment with phenobarbital was installed. At that time,
physical examination showed coarse facial features, high-
arched, thick eyebrows, bulbous nasal tip, micrognathia,
posteriorly rotated ears with attached lobes, flared thorax,
inverted nipples, hepatosplenomegaly, broad thumbs, mild
ichthyosis and muscular hypotonia. (Figure 1A, B, C, D).
At 11 days of life she presented two episodes of obstruct-
ive respiratory arrest after stridor, treated with ventilation.
The otolaryngologist’s evaluation revealed the presence of
a cystic formation of the vallecula, which was removed
surgically with resolution of the episodes of apnoea.
Because of the coarse facial features, hypertrichosis,
and hepatosplenomegaly, a lysosomal storage disorderFigure 1 Phenotype. A: coarse face, high-arched, thick eyebrows,
bulbous nasal tip and mild ichthyosis. B: micrognathia, posteriorly rotated
ears with attached lobes. C: abdominal ichthyosis. D: ichthyosis of the
lower limb and feet.was considered. There was an increased urinary excretion
of glycosaminoglycans (1101 μg/mg creatinine; normal
range, 30–200), with chondroitin sulfate (+++), dermatan
sulfate (+++) and heparan sulfate (++) on electrophoresis.
Enzyme activitiy testing in leucocytes showed deficiency
of arylsulfatase A (0.0 nM/mg/h; n.v. 40–270), arylsulfa-
tase B (0.0 nM/mg/h; n.v. 70–126), iduronate sulfatase
(0.9 nM/mg/4 h; n.v. 51–123) and galactose 6 sulfatase
(0.6 nM/mg/17 h; n.v.20-27). This pattern was diagnostic
of Multiple sulfatase deficiency (MSD). Molecular analysis
of the gene SUMF1 revealed two so far undescribed
heterozygous mutations: c.191C > A s. S64X in exon 1
and c.818A >G p.D273G in exon 6. The first heterozygous
mutation was also demonstrated in the girl’s mother, while
the second one was identified in the girl’s father.
The karyotype was normal, 46,XX. The echocardiography
and EEG were normal; abdominal ultrasound showed
hepatomegaly; brain magnetic resonance imaging (MRI)
showed dilated lateral ventricles with an enlarged cisterna
magna, demyelination of the white matter, partial corpus
callosum hypoplasia with hypothrophy of the splenium
and dismorphism of the hippocampum. Skeletal radio-
graphy revealed a pattern of dysostosis multiplex with
hypoplasia of L2, lumbar kyphosis and platyspondyly of
the cervical vertebral bodies; broad ribs; broad and hypo-
plastic first metacarpals, pointing of the second and
third metacarpals, irregularity of the distal radial and
ulnar metaphysis (Figure 2A, B, C, D). The ABR examin-
ation showed mild hypoacusia.
The child presented global developmental delay: could
hold head up only at the age of 10 months, at the age of
12 months she was still hypotonic, with limited and
jerky movements and it was impossible to meet her gaze.
She developed dorso-lumbar kyphosis and owing to L2
hypoplasia she had to wear a orthopaedic corset.
She was seen again in our Clinical Genetics Unit at
24 months of age. Her head circumference was 45 cm
(50th centile), length 66 cm (<3rd centile), and weight
6.406 Kg (<<3rd centile). Her psychomotor development
was severely delayed and she uttered no words. At the
age of 24 months she could not sit up unaided.
Discussion
Multiple sulfatase deficiency is a rare autosomal recessive
inborn error of metabolism affecting post-translational ac-
tivation of sulfatases by the formylglycine generating en-
zyme (FGE). Due to mutations in the encoding SUMF1
gene, FGE’s catalytic capacity is impaired, resulting in
reduced cellular sulfatase activities [9]. More than 30
different SUMF1 mutations are known, most of them mis-
sense mutations that affect stability and residual molecular
activity of mutant FGE, which both determine MSD
disease severity [10]. A variable residual activity of the
different sulfatases has been described [1,11].
Figure 2 X-Rays. A: broad and hypoplastic first metacarpals, pointing of the second and third metacarpals, irregularity of the distal radial and
ulnar metaphysis. B: platyspondily of the cervical vertebral bodies. C: hypoplastic vertebral body of L2, lumbar kyphosis. D: broad ribs.
Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 3 of 4Few studies were able to show a correlation of both
residual activity and stability of FGE variants with the
clinical presentation of selected MSD patients. Patients with
drastic impairments of both FGE stability and residual
enzyme activity displayed the most severe clinical pheno-
type whereas the mildest phenotype was associated with the
highest residual FGE activity among the studied variants.
It is now possible to establish a genotype/phenotype
correlation for MSD and to roughly predict the clinical
course for patients with the studied SUMF1 mutations.
Missense mutations affecting crucial functional or struc-
tural residues in FGE, as well as nonsense ones, will cause
severe forms of the disease, whereas missense mutations
not fully abrogating a functional conformation of the FGE
protein will lead to attenuated forms [6].
Different types of MSD can be distinguished according
to the age of onset: neonatal, late infantile (0 to 2 years,
severe or LIS and mild or LIM), and rare juvenile (2 to
4 years, mild) [8].
The clinical picture of MSD combines symptoms of
the different sulfatase deficiencies. Patients show neuro-
logical deterioration and a neurodegenerative course of
disease similar to metachromatic leukodystrophy. Develop-
ment delay, dysmorphism and organomegaly are present
as found in various mucopolysaccharidoses [6]. Skeletal
abnormalities remind one of Chondrodysplasia punctata
type 1 and skin changes of X-linked ichthyosis [1].
The onset of symptoms in early infancy is associated
with poor chances of survival; conversely, when features
of the disease appear in late infancy, patients survive
longer.
In general it is rare to carry out a diagnosis of storage
disease in newborns apart from I-cell disease also known
as mucolipidosis II, which is a condition with a severeclinical course, typical radiological aspects and fibroblast
inclusions. Other symptoms include hyperplastic gums,
thoracic deformities and congenital hip dislocation which
are evident in newborn age. In the other storage diseases
the symptoms are not so evident in the newborn age.
The diagnosis of MSD may not be simple due to the
rarity of the condition: in our case the features which led
us to suspect the diagnosis were the MPS-like phenotype,
the radiological signs compatible with “dysostosis multi-
plex” and especially the cutaneous features. The child had
no signs of chondrodysplasia punctata, in particular no
epiphyseal stippling.
Indeed the presence of ichthyosis can be a very useful
indicator in identifying the condition and can be the best
marker of the disease in newborns.
Our patient had typical features of neonatal MSD in-
cluding neonatal hypotonia, coarse face, mild deafness,
visceromegaly, hypoplastic vertebral bodies and delayed
psychomotor development.
It was demonstrated that the phenotypic outcome de-
pends on both residual FGE activity as well as protein
stability [6]. Another neonatal case was described which
showed all the clinical symptoms of the condition and a
quick worsening course of the disease: he presented two
nonsense mutations leading to almost fully abrogated
FGE activity, highly unstable FGE protein and nearly
undetectable sulfatase activity [6]. Our case presents a
missense mutation along with a nonsense mutation.
In fact we have identified two so far undescribed SUMF1
mutations (c.191C >A; p.S64X and c.818A >G; p.D273G),
resulting in a severe clinical phenotype with early onset,
but which allow survival beyond one year of life, in con-
trast with what has been reported in literature up to this
point. She has a serious clinical aspect, but probably less
Garavelli et al. Italian Journal of Pediatrics  (2014) 40:86 Page 4 of 4severe than that described by Schlotawa and is still alive at
the age of 2 years.
MSD is still an untreatable disease. Thus, potential
treatment approaches, and also genetic counselling,
directly depend on thorough analyses of the functional
consequences of human SUMF1 mutations on the clinical
and biochemical phenotype.
Understanding better the molecular mechanism at the
root of this condition could aid the identification of the
most appropriate therapeutic approach of MSD in the
near future.
Conclusion
In conclusion, our patient illustrates well the main clinical
features to suspect this condition in the newborn age,
ichthyosis in particular, the wide spectrum of clinical
manifestations and biochemical abnormalities of this rare
disease. This case serves to highlight the importance of
full and detailed evaluation of all patients with rare dis-
orders and the need for continued updates of suggested
surveillance for these diseases.
Consent
Written informed consent was obtained from the patient’s
guardian/parent/next of kin for the publication of this
report and any accompanying images”.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LG and AI wrote the manuscript, LG, LS, GG, SB, NM, DF, LZ, TG, LP, AW,
SR, II, LI, CG, SB, AS-F and OG participated in the diagnostic process, AS-F
evaluated the X-Rays, SP and AB carried out the molecular genetic tests.
All authors read and approved the final manuscript.
Acknowledgements
The authors wish to thank the co-operating family-members for the necessary
medical data and photographs for publication as well as the photographers
Marco Bonazzi and Luca Valcavi. This research was funded in part by
Fondazione Manodori.
Author details
1Clinical Genetics Unit, Obstetric and Pediatric Department, Istituto di
Ricovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova,
Reggio Emilia, Italy. 2Pediatrics Unit, UNIVPM, Ancona, Italy. 3Department of
Medical and Surgical Sciences of Childhood and Adult, University of Modena
and Reggio Emilia, Modena, Italy. 4Neonatal Intensive Care Unit, Obstetric
and Pediatric Department, Istituto di Ricovero e Cura a Carattere Scientifico,
Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. 5Pediatric Neurology
Unit, Obstetric and Pediatric Department, Istituto di Ricovero e Cura a
Carattere Scientifico, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
6Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino
111, 80131 Naples, Italy. 7Department of Medical Genetics, Policlinico
Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy. 8Deparment of
Pediatrics, University of Parma, Parma, Italy. 9Department of Pediatrics, Centre
Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne,
Switzerland. 10Department of Molecular and Human Genetics, Baylor College
of Medicine, Houston, TX 77030, USA. 11Jan and Dan Duncan Neurological
Research Institute, Texas Children Hospital, Houston, TX 77030, USA.
12Medical Genetics, Department of Translational Medicine, Federico II
University, Via Pansini 5, 80131 Naples, Italy.Received: 11 August 2014 Accepted: 28 October 2014
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Multiple sulfatase deficiency with neonatal manifestation

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Archivio istituzionale della Ricerca -  Università degli Studi di Parma

MULTIPLE SULFATASE DEFICIENCY WITH NEONATAL MANIFESTATION

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Multiple sulfatase deficiency with neonatal manifestation.

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