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|LETTER TO EDITOR
|Year : 2015 | Volume
| Issue : 4 | Page : 612-615
Mucopolysaccharidosis type I with craniosynostosis
Nishanth Sadashiva1, Parayil Sankaran Bindu2, Vani Santosh3, Bhagavatula Indira Devi1, Dhaval Shukla1
1 Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
|Date of Web Publication||4-Aug-2015|
Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sadashiva N, Bindu PS, Santosh V, Devi BI, Shukla D. Mucopolysaccharidosis type I with craniosynostosis. Neurol India 2015;63:612-5
Mucopolysaccharidosis type I (MPS-I) is a rare autosomal recessive disease, occurring due to defective degradation of glycosaminoglycan (GAGs) by mutations of the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA). It causes subsequent accumulation of heparan and dermatan sulfate in various tissues and organs. The phenotypic spectrum of the disease varies from Hurler syndrome (with neurological involvement) to the more attenuated Hurler-Scheie syndrome (skeletal and visceral involvement) and Scheie syndrome (minimal visceral but nonnegligible skeletal involvement).  Patients with MPS-I have a reduced life expectancy. Without treatment, patients with the most severe form of the disease have a median survival of 6.8 years.  Patients with a more attenuated form of the disease survive upto adolescence or adulthood. Affected children appear normal at birth and develop these morphologic changes in the first few months. The diagnosis involves demonstrating increased amounts of GAGs in the urine. Confirmation can be done by enzyme assay demonstrating a deficient enzymatic activity in leukocytes or fibroblasts, or by a molecular genetic testing of the IDUA gene. Enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy are the therapeutic modalities available. 
Though skeletal and neural involvement are known, craniosynostosis with MPS-I is rare. We describe a case of craniosynostosis associated with MPS-I diagnosed with electron microscopy.
A 2-year-old girl from eastern India presented with an abnormal shape of the head since 6 months of age. She had delayed motor milestones, was able to walk independently, was speaking short sentences, and was playful. She had a history of recurrent respiratory tract infections with atopic dermatitis. Examination showed the presence of scaphocephaly with an antero-posterior diameter of 17 cm and a transverse diameter of 12 cm. The head circumference was 50.5 cm, and the anterior fontanel was closed.
She had dysmorphic facial features, macroglossia, a short neck, a low hair line, a high arched palate, corneal haziness, Mongolian spots over back, exaggerated thoracic kyphosis, and short stout fingers. There was no papilledema on fundoscopic examination. The motor examination was normal. The social age was 2 years and 6 months, and the social quotient was 125 on Vineland Social Maturity Scale. Ultrasound abdomen showed moderate hepatomegaly. The echocardiogram showed mitral valve prolapse with moderate mitral regurgitation and tricuspid valve collapse with mild tricuspid regurgitation. The left ventricular function was normal with an ejection fraction of 65%.
A battery of tests for metabolic storage disorders was done. The urine spot test for mucopolysaccharidosis, ferric chloride, dinitrophenyl hydrazine, cyanide nitroprusside, and benedict tests were negative. A repeat test for mucopolysaccharidosis was also negative. The screening for inborn errors of metabolism with tandem mass spectrometry revealed normal amino acids and acyl carnitine profile. The lysosomal enzyme levels, arylsulfatase A, total serum hexosaminidase, hexosaminidase A and hexosaminidase B percentages were normal.
The head computed tomography scan with surface shaded display reconstruction showed a fusion of metopic, sagittal, and lambdoid sutures. The frontal compensation was more than occipital [Figure 1]. Magnetic resonance imaging showed bilateral frontotemporal atrophy but the degree of myelination was reported to be adequate for the age.
|Figure 1: (a - c) Magnetic resonance image showing scaphocephaly with frontal bossing and bilateral frontotemporal atrophy; (d - f) computed tomography surface shaded display showing craniosynostosis involving metopic, sagittal and bilateral lambdoid sutures|
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The anterior pi procedure was done for metopic and sagittal stenosis. Although she had both lambdoid and posterior sagittal ("Mercedes-Benz") craniosynostosis, the posterior compensation was not significantly disfiguring, hence posterior skull vault reconstruction was not performed. The intracranial pressure (ICP) measured during the surgery was normal. Temporal scalp skin biopsy was taken during surgery.
Patient made an uneventful recovery. Histopathological examination of skin biopsy appeared normal. However, electron microscopy showed membrane bound lysosomal vacuoles studded with fibrillar material in myoepithelial cells of eccrine glands confirming MPS [Figure 2]. Postoperatively, the patient and her relatives were referred for genetic counseling and possible enzyme replacement therapy. The parents could not afford further treatment. After 8 months of surgery, she had respiratory distress, abdominal distension, and generalized edema for which she was treated at a hospital in her native place. She developed multiorgan dysfunction and ultimately succumbed after 8 days of hospitalization.
|Figure 2: (a) Higher magnification (×9300) skin biopsy shows membrane bound lysosomal vacuoles within myoepithelial cells of eccrine glands; (b) higher magnification (×9300) shows fibrillar material within membrane bound lysosomal vacuoles in myoepithelial cells of eccrine glands characteristic of mucopolysaccharidosis|
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Various manifestations with different reasons for tissue dysfunction have been described in MPS-I. The skeletal dysplasia results from a lack of skeletal remodelling and ossification abnormalities owing to abnormal deposition of GAGs in bone and cartilage. Thoraco-lumbar gibbus, oar-shaped ribs, thickened clavicles, flaring iliac wings, hip dysplasia and coxa valga have been described,  of which our case had an exaggerated thoracic kyphosis and short stout fingers.
Cardiac valvular disease, endocardial fibroelastosis, arrhythmias, congestive heart failure, aortic stenosis and myocardial ischemia may occur.  Our case had mitral and tricuspid valve prolapse with regurgitation. Respiratory problems are due to GAGs infiltrating the airway soft tissues and thoracic cage.  Ophthalmological features comprise corneal clouding, glaucoma, retinal degeneration, optic disc swelling, pseudo-exophthalmos, amblyopia, strabismus and refractive errors.  Our case had only haziness of cornea. Severe form of MPS-I may have developmental delay, particularly of speech, which is then followed by a decline in cognitive, visual and auditory function.  However, our case had normal development. Other central nervous system manifestations include brain atrophy, thickened meninges, prominent subarachnoid spaces, patchy white matter signal abnormality, multiple perivascular spaces and hydrocephalus.  Our case had brain atrophy, and normal intracranial pressure. She, therefore, did not have any manifestations suggestive of a severe form of MPS-I.
Scaphocephaly is described as one of the features of MPS similar to that seen in other metabolic and genetic diseases.  Manara et al. reported 33 Italian patients with MPS-II, out of which seven had craniosynostosis. Children with MPS and craniosynostosis usually do not undergo surgery.  Ziyadeh, et al. reported the first case of MPS-I in a 2.5-year-old girl with craniosynostosis, who was treated surgically.  The argument for surgery was the presence of papilledema indicating raised ICP, which was confirmed using ICP monitoring during surgery. The fundoscopy can be challenging in children with MPS due to corneal depositions, and discriminating between optic disc swelling due to raised ICP (either resulting from skull deformity or associated with MPS) and optic disc infiltration by GAGs is difficult.
In our case, we were not able to confirm a diagnosis of MPS through the available investigations and the child's development was normal without significant comorbidities. We, therefore, offered surgery. We did not know the prognosis of the disease. We hoped that the child might have a milder variant of metabolic storage disorder with a good life expectancy. The diagnosis was confirmed only after surgery through electron microscopy of the skin biopsy. One can argue that a skin biopsy could have been done before surgery, and a major surgery could have been avoided. She was well until 8 months after surgery, but unfortunately died of unrelated severe sepsis.
This is the second case of MPS-I with craniosynostosis described in the literature who underwent surgery. The decision for surgery should be taking into account, the characterization of the metabolic disorder, its course, prognosis, and life expectancy. All of these factors were favorable in our patient; therefore, surgery for craniosynostosis in a child with MPS-I was performed.
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[Figure 1], [Figure 2]