Molecular Genetics and Metabolism 103 (2011) 135–137

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Molecular Genetics and Metabolism

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Combined Hurler and Sanfilippo syndrome in a sibling pair

Angela Sun a,⁎, John J. Hopwood b, Jerry Thompson c, Stephen D. Cederbaum d

a UCLA Intercampus Medical Genetics Training Program, Cedars-Sinai Medical Center, Los Angeles, CA, USAb Lysosomal Diseases Research Unit, A Research Centre of SA Pathology, Women's and Children's Hospital, North Adelaide, SA, Australiac Department of Genetics, University of Alabama at Birmingham, AL, USAd Departments of Psychiatry, Pediatrics and Human Genetics, UCLA Center for the Health Sciences, Los Angeles, CA, USA

⁎ Corresponding author at: 8700 Beverly Blvd, PACT 4E-mail address: angela.sun@cshs.org (A. Sun).

1096-7192/$ – see front matter © 2011 Elsevier Inc. Aldoi:10.1016/j.ymgme.2011.02.011

a b s t r a c t

a r t i c l e i n f o

Article history:Received 28 December 2010Received in revised form 16 February 2011Accepted 16 February 2011Available online 22 February 2011

Keywords:Hurler syndromeSanfilippo syndromeEnzyme replacement therapyPsychosocial issues

Themucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involvedin the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) areamong the more common diseases in the group, each occurring with an incidence of approximately 1 in100,000. We present a case of siblings, born of a consanguineous union, affected with both MPS I andMPS IIIa.The diagnoses were confirmed with fibroblast enzyme assays and sequence analysis of the genes, whichidentified homozygous mutations in IDUA and SGSH. We discuss their clinical features and course andexamine the psychosocial aspects of their case, specifically, the decision-making process that the medicalteam and family faced regarding treatment with enzyme replacement therapy.

, Los Angeles, CA 90048, USA.

l rights reserved.

© 2011 Elsevier Inc. All rights reserved.

1. Introduction

The mucopolysaccharidoses (MPS) are lysosomal storage disorderscaused by defects in the enzymes involved in the degradation ofglycosaminoglycans. Hurler syndrome and Sanfilippo syndrome areamong the more common diseases in the group, each occurring with anincidence of approximately 1 in 100,000 [1,2]. Individuals with Hurlersyndrome or MPS I have deficiency of the enzyme alpha-L-iduronidaseand present with developmental delay, coarse facial features, upperairway obstruction, respiratory infections, cardiac disease, and hepatos-plenomegaly [3]. There are four subtypes of Sanfilippo syndrome orMPSIII, all of which are caused by deficiency of enzymes involved in thebreakdown of heparan sulfate. Patients with MPS III typically manifestwith neurologic rather than somatic symptoms such as severe behavioralproblems, poor sleep, and progressive neurological deterioration [3]. Wepresent a case of siblings affectedwith bothMPS I andMPS III and discusstheir clinical features and course.

2. Case reports

2.1. Case 1

The proband is an 8-year-old male of Mexican origin who was theproduct of an uncle–niece union. He was born at 32 weeks gestationalage to a 20-year old gravida 1 para 1 mother via normal spontaneousvaginal delivery. His birth weight was 3 pounds and 12 ounces. During

the first year of life, he was noted to have developmental delay andcoarse facial features. Hewas clinically diagnosedwithHurler syndromeat age 1.5 years. Urinary quantitation of glycosaminoglycans showed127 mg/g creatinine of uronic acid by the orcinol reaction (nl. 10.7±8.0) and 449 mg/g creatinine by the carbazole reaction (nl. 16.9±9.9),giving a carbazole to orcinol ratio of almost 3, which is indicative ofexcess heparan sulfate as compared with dermatan sulfate. Theelectrophoresis which revealed a strong band of heparan sulfate andslightly less chondroitin sulfate was confirmatory of this conclusion. N-sulfated hexosamine was 126 mg/g creatinine (nl. 15.8±12). Enzymeanalysis onfibroblasts showed10% residual alpha-L-iduronidase activityand no detectable activity for heparan N-sulfatase. Molecular genetictesting revealed a homozygous c.923TNC (L308P)mutation in the IDUAgene, which has not been previously reported, and a homozygousc.268GNA (G90R) mutation in the SGSH gene, a known pathogenicvariant. Thus, he was diagnosed with combined Hurler syndrome andSanfilippo syndrome type A.

During early childhood, the patient had significant problems withgastroesophageal reflux due to a hiatal hernia. He underwent a Nissenfundoplication anda later revision.Healsohadanumbilical hernia repair.He had multiple hospital admissions for pneumonia and asthmaexacerbations. He also had recurrent otitis media, and pressureequalization tubes were placed on multiple occasions. He developedbilateral moderate to severe hearing loss and was prescribed hearingaids. He had a tonsillectomy and adenoidectomy at age 5 years, afterwhich his breathing improved.

An abdominal ultrasound at 5 years of age showed an enlarged livermeasuring 14.1 cm. His spleen remained normal in size. An echocardio-gram at 17 months of age showed mild concentric left ventricularhypertrophy, and at 4 years of age showed aminimal septal bulge into the

136 A. Sun et al. / Molecular Genetics and Metabolism 103 (2011) 135–137

left ventricular outflow tract and otherwise normal cardiac anatomy andfunction. AnMRIof thebrain at age 2 yearswasnormal. He reportedlyhada normal ophthalmologic examination at 3 years of age, and at age 8 hasnot developed corneal clouding.

The patient had mild orthopedic complications. A skeletal survey at2 years of age showed early signs of dysostosis multiplex including aJ-shaped sella, short and slightly expanded metacarpal bones with thincortices, and a narrow iliac basewith rounded iliac wings. A chest X-rayat age 7 revealed paddle-shaped ribs and short, thickened clavicles. Atage 4 years, he began to have increasing joint stiffness, most notably inhis ankles, which resulted in toe-walking. He underwent a heel cordreleasewhenhewas6 years old.With age, hedeveloped contractures atthe knees forwhichhewasprescribedbraces. Hebegan losinghis abilityto ambulate between ages 6 and 7 years.

In terms of physical growth, the patient's height remained in the10–50th percentiles up to age 6, after which his linear growth beganto fall off. His weight was at or above the 90th percentile between ages2 and 5 years but by age 8 was below the 5th percentile. His headcircumference was greater than 95th percentile at age 3 years and25–50th percentiles at age 8 years.

Developmentally, he remained globally delayed. His milestones,corrected for prematurity, were as follows: he sat at 9 months, begancruising at 14 months, and walking at 19 months. He began babblingaround 8 months of age. At 17 months, he had 10 words. A formaldevelopmental assessment was done at 22 months of age, and he wasfound tohave adevelopmental quotient of 50. By 3.5 years of age, hewasonly using a few words and gestures, and at 5 years, he was nonverbal.He also had severe behavioral problems including extremehyperactivityfor which he was treated with clonidine and methylphenidate duringearly childhood. The behavioral problems began to abate around 4 yearsof age.

Regarding medical treatment, the patient was evaluated for a bonemarrow transplant but was determined to be ineligible due to his lowdevelopmental quotient. He was started on enzyme replacementtherapy (ERT) for iduronidase deficiency at age 3 years. However, hissevere hyperactivity often precluded therapy as he could not sit stillduring the infusions, and the intravenous access catheter infiltrated onnumerous occasions. Given his mild somatic symptoms, the concurrentdiagnosis of Sanfilippo syndrome, a lethal condition, as well as thedifficulty his family hadwith his complexmedical care, the decisionwasmadewith the family's participation and accord to discontinue ERT andto treat only those problems that would improve his quality of life. Hewas on ERT for a total of 3 years.

2.2. Case 2

The proband's sister is a 2-year-old female born of the sameconsanguineous union. The pregnancy was uncomplicated. The motherdeclined prenatal genetic testing. The patient was born full term viacesarian section with a birth weight of 7 pounds and 6 ounces. Afterbirth, molecular genetic testing revealed the same homozygousmutations in the IDUA and SGSH genes as her brother. Thus, she wasalso diagnosed with combined Hurler syndrome and Sanfilipposyndrome type A.

Her physical growth has not been impaired. All growth parametersat 2 years of age are above the 90th percentile. Her primary medicalproblem is recurrent otitis media. She has had more than 10 earinfections. Like her brother, she was also diagnosed with bilateralmoderate to severe hearing loss. She has not developed cornealclouding yet. In terms of organ involvement, her liver was palpable7 cm below the costal margin at age 2 years. An echocardiogram at thesame age showed thickened mitral leaflets and mild to moderateregurgitation. Developmentally, she is mildly delayed, mainly in thelanguage domain. Her motor milestones have been normal thus far.

Given the conclusion to discontinue enzyme replacement therapyin her brother, the decision was made, again with the participation of

the patient's mother, not to initiate ERT unless she developed somaticsymptoms that could be alleviated with treatment.

3. Discussion

The mucopolysaccharidoses, as with most inborn errors of metab-olism, are rare in the general population. Consanguinity may uncoverrecessive disorders due to the increased number of mutant allelesshared by a couple with a common ancestor. In the case of the twosiblings in this report, both parents were carriers of MPS I and MPS III,which is an extraordinary circumstance. There are instances ofindividuals affected with more than one recessive condition, usually inthe context of consanguinity (authors' personal experience). However,for an individual to carry aberrant alleles for two types of MPS is quiteexceptional. Furthermore, the chance for such carrier parents to havetwo children affected with both disorders is 1/256.

Phenotypically, the older brother had somaticmanifestations ofHurlersyndrome and neurobehavioral symptoms of Sanfilippo syndrome,although the lack of corneal clouding would seem to indicate a mild orattenuated formofHurler syndrome. It is interesting to speculatewhethera combination of MPS disorders would result in a more severe form ofdisease, perhaps with novel features. Given the clinical spectrumassociated with varying degrees of residual enzyme activity, the ultimatephenotype would be difficult to predict. However, our patient's featuresappear to represent a true overlap of the two individual conditions.

The decision to discontinue ERT in the older brother may be viewedby some as inappropriate or unethical. However, it is important toremember that this patient and his family are in a truly unique position.Firstly, he is affectedwith two conditions, both ofwhich are progressive,and one of which is uniformly fatal. Treatment of one does notameliorate thedamage causedby theother. Even in patientswithHurlersyndrome alone, ERT is not curative; it merely slows the progression ofdisease [4–6]. In a patient who has a second condition that is lethal, ERTmay simply delay the inevitable outcome and prolong the period ofunrelenting deterioration, duringwhich time the patient's quality of lifemay be quite poor. Secondly, complex social problems permeated thisfamily. The mother willingly renewed her relationship with her uncle,knowing the severity of her son's condition. She is a young, singlemother and had tremendous difficulty with the complex medical carethat her children required. Keeping appointments was a challenge, aswere, ultimately, theweekly enzyme infusions. Lastly, andperhapsmostimportantly, the patient was not experiencing significant somaticsymptoms. Therefore, the medical team, in conjunction with thepatient's mother, chose to discontinue ERT. Likewise, ERT was notinitiated for the younger sister.

Wehavemaintaineda close relationshipwith the family andcontinueto followboth children at regular intervals. Such a unique family as theirsreminds us of the tragic nature of certain genetic conditions and teachesus to bemindful of both the science and art of medicine, themedical andpsychosocial aspects of care.

Acknowledgments

We would firstly like to thank the patients and their mother forallowing us to participate in their care. We are also grateful to Dr. RalphLachman for his radiologic insights and expertise and to our colleagues atUCLAwho have played a critical role in the ongoing care of these patients.

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[3] Inborn Metabolic Diseases, in: J. Fernandes, J.M. Saudubray, G. van den Berghe, J.H.Walter (Eds.), 4th ed., Springer, 2006.

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