An Early Presentation of a Genomic Variant of Mucopolysaccharidoses II in a Female Newborn Baby

Mucopolysaccharidoses II is a X-linked genetic disorder caused by the deficiency of lysosomal enzyme Iduronate sulfate sulfatase due to mutations of Iduronate 2-sulfatase (IDS) gene which results in accumulation of intralysosomal glycosaminoglycan. X inactivation and gene alterations are known to cause this entity in a female child. We report an unusual case of missense mutation of IDS gene in heterozygous variant with dominant expression in a female neonate presented in early newborn period with incurable severity. Xlinked recessive (heterozygous) missense mutation of Exon 8 in IDS gene confirmed a case of Mucopolysaccharidoses II by Sanger sequencing.


M ucopolysaccharidoses II (MPS II) is also known as Hunter
Syndrome and was fi rst described in 1917 by Hunter C. 1 MPS II in a female child is a recognised entity and several cases have been reported with variable clinical presentation and outcome. [2][3][4][5] The multi exon deletion and missense mutation on specifi c location are the major deciding factors for severity and early presentation of the disease. 6 The case reported here presented in newborn period with utmost severity in a female neonate.

Case Report
A female neonate, fi rst product of non-consanguineous marriage was born through thick meconium stained liquor and required resuscitation at birth. Birth weight of the baby was 2.34 kg and head circumference was 33 cm. Antenatal sonography scan was unremarkable. The baby had multiple blueberry muffi n spots, ecchymosis, dilated tortuous vein over scalp and Mongolian spots [ Figure 1].
Crackles were heard on both sides of chest and the abdomen was distended due to enlarged liver and spleen. Apt test in gastric lavage was positive for neonatal blood. Blood investigation at birth reported as platelets-35,000, reticulocytes-8.2%, international normalised ratio-4.9 and elevated liver enzymes. Direct anti-globulin test was negative.
Kidigram showed cardiomegaly and only midline bowel gas due to massive hepatosplenomegaly. At six hours of life, the baby started to have profuse bleeding from all natural orifi ces. The baby was ventilated and all possible intensive management were instituted but she continued to deteriorate and succumbed to her illness.
The clinical presentation prompted to investigate for congenital infections, metabolic disorders and neonatal malignancy. Blood samples were taken before blood and component transfusion. TORCH titer of the baby was nonreactive. There were no abnormal cells in peripheral blood smear. Suspecting a metabolic disorder Clinical Exon Sequencing test was done which revealed X-linked recessive variant (heterozygous) missense mutation c. C1083G (p.Phe 361Leu) of Exon 8 (NM_000202) in the IDS gene. Additional fi ndings were also reported as recessive (compound heterozygous) variant (c.C3659t/p.Ser 1220 Phe and c.G7181A/) in NBEAL2 gene and dominant (heterozygous) missense variant (c.G2511C/p.Gln 837 His) in ITGA2B gene. This was further confi rmed by Sanger Sequencing (Figure 2).

Discussion
MPS II heterozygous females are rarely aff ected unless either there is a simultaneous presence of two mutant alleles or a coincidental genetic defect leading to skewed X-inactivation or hemizygosity in heterozygote condition with dominant expression of the mutant IDS allele. [7][8][9] In MPS II the pattern of skewed X-chromosome inactivation is a major factor in determining the phenotype in heterozygotes and aff ected females. 7,10 As a rule, gene deletion correlates with clinical severity and age of presentation, whereas missense mutation of IDS gene alone is responsible for less severe variant. 8 In contrast to this general rule, the missense mutation can also present with variable phenotype and as a fact, clinical severity depends on the location of specifi c mutation. 6 The index case had X-linked recessive variant (heterozygous) missense mutation c.C1083G (p.Phe 361Leu) of Exon 8 (NM_000202) in the IDS gene along with compound heterozygous variant in NBEAL2 gene and dominant heterozygous missense variant.
Extra medullary haematopoiesis in dermis is seen as blueberry muffi n eruptions which are reddish blue or magenta coloured non blanching purpuric lesions. Such extra medullary haematopoiesis occurs as a manifestation of increased demand of haematopoiesis which may be due to loss of cellular blood element or dysfunction of bone marrow. The diff erential diagnosis of blueberry muffi n lesions is huge. In our case the common possible causes of blueberry muffi n lesions presenting at birth were ruled out like congenital rubella and cytomegalovirus infections and blood dyscrasias. Some neonatal malignant conditions can also have the similar dermal lesions at birth, as it is seen in congenital monoblastic leukemia. Peripheral blood smear of this baby was not suggestive of malignancy but fl ow cytometry defi nitely would have been a better choice for exclusion of haematological malignancy.
Structural alteration and simultaneous presence of more than two mutant alleles in heterozygous variant with dominant expression were presumably responsible for the severity and early presentation in this case. Analysis for X chromosome inactivation was not done due to fi nancial constraints, which could have better explain the reason for early presentation and severity of the disease in this case. Parental genomic sequencing was also not done to fi nd out whether the obtained variant in patient was inherited or de-novo mutation. This was a limitation to this case.

Conclusion
Inborn errors of metabolism should be considered in diff erential diagnosis of a severely ill new born baby. We reported this case to promulgate the fact that contrary to presently known genetic substantiation, a missense mutation of IDS gene may also lead to severe and early presentation of MPS II in neonatal age even in a female baby.