Skip to main content

Mucolipidosis II presenting as severe neonatal hyperparathyroidism


Mucolipidosis II (ML II or I-cell disease ) (OMIM 252500) is an autosomal recessive lysosomal enzyme targeting disorder that usually presents between 6 and 12 months of age with a clinical phenotype resembling Hurler syndrome and a radiological picture of dysostosis multiplex. When ML II is severe enough to be detected in the newborn period, the radiological changes have been described as similar to hyperparathyroidism or rickets. The biological basis of these findings has not been explored and few biochemical measurements have been recorded. We describe three unrelated infants with ML II who had radiological features of intrauterine hyperparathyroidism and biochemical findings consistent with severe secondary neonatal hyperparathyroidism (marked elevation of serum parathyroid hormone and alkaline phosphatase levels). The vitamin D metabolites were not substantially different from normal and repeatedly normal calcium concentrations excluded vitamin D deficiency rickets and neonatal severe hyperparathyroidism secondary to calcium-sensing receptor gene mutations (OMIM 239200). The pathogenesis of severe hyperparathyroidism in the fetus and newborn with ML II is unexplained. We hypothesize that the enzyme targeting defect of ML II interferes with transplacental calcium transport leading to a calcium starved fetus and activation of the parathyroid response to maintain extracellular calcium concentrations within the normal range. Conclusion: Newborns with mucolipidosis II can present with radiological and biochemical signs of hyperparathyroidism. Awareness of this phenomenon may help in avoiding diagnostic pitfalls and establishing a proper diagnosis and therapy.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7



alkaline phosphatase


calcium-sensing receptor

1,25D :

1,25-dihydroxyvitamin D


mucolipidosis II


neonatal severe hyperparathyroidism

25OHD :

25-hydroxyvitamin D


parathyroid hormone


parathyroid hormone-related peptide


  1. Babcock DS, Bove KE, Hug G, Dignan PSJ, Soukup S, Warren NS (1986) Fetal mucolipidosis II (I-cell disease): radiologic and pathologic correlation. Pediatr Radiol 16: 32–39

    CAS  PubMed  Google Scholar 

  2. Bai M, Pearce SHS, Kifor O, Trivedi S, Stauffer UG, Thakker RV, Br EM, Steinmann B (1997) In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+ -sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest 99: 88–96

    CAS  PubMed  Google Scholar 

  3. Beck M, Barone R, Hoffmann R, Kratzer W, Rakowsky T, Nigro F, Fiumara A (1995) Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet 47: 191–199

    CAS  PubMed  Google Scholar 

  4. Bocca G, Noordam C, Wevers RA, de Jong JGN, van der Meer W, de Keijzer MH, Korver CRW, Smeitink JAM (2000) I-cell disease presenting with severe hypophosphatemia and cardiomyopathy. Neuropediatrics 31: 49–50

    Article  CAS  PubMed  Google Scholar 

  5. Cipolloni C, Boldrini A, Donti E, Maiorana A, Coppa GV (1980) Neonatal mucolipidosis II (I-cell disease): clinical, radiological and biochemical studies in a case. Helv Paediatr Acta 35: 85–95

    CAS  PubMed  Google Scholar 

  6. Cole DEC, Janici N, Salisbury SR, Hendy GN (1997) Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with inactivating Alu insertion mutation of the calcium–sensing receptor gene. Am J Med Genet 71: 202–210

    Article  CAS  PubMed  Google Scholar 

  7. Herman TE, McAlister WH (1996) Neonatal mucolipidosis II (I-cell disease) with disharmonic epiphyseal ossification and butterfly vertebral body. J Perinatol 16: 400–402

    CAS  PubMed  Google Scholar 

  8. Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11: 389–394

    Article  CAS  PubMed  Google Scholar 

  9. Hochman JA, Treem WR, Dougherty F, Bentley RC (2001) Mucolipidosis II (I-cell disease) presenting as neonatal cholestasis. J Inherit Metab Dis 24: 603–604

    Article  CAS  PubMed  Google Scholar 

  10. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8: 277–289

    CAS  PubMed  Google Scholar 

  11. Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM (1996) Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 93: 15233–15238

    Article  CAS  PubMed  Google Scholar 

  12. Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM (1998) Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J Clin Invest 101: 2812–2820

    CAS  PubMed  Google Scholar 

  13. Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM (2001) Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 107: 1007–1015

    CAS  PubMed  Google Scholar 

  14. Kovacs CS, Chafe LL, Fudge NJ, Friel JK, Manley NR (2001) PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. Endocrinology 142: 4983–4993

    Article  CAS  PubMed  Google Scholar 

  15. Lemaitre L, Remy J, Farriaux JP, Dhondt JL, Walbaum R (1978) Radiological signs of mucolipidosis II or I-cell disease. Pediatr Radiol 7: 97–105

    CAS  PubMed  Google Scholar 

  16. Leroy JG, Demars RI (1967) Mutant enzymatic and cytological phenotypes in cultured human fibroblasts. Science 157: 804–806

    CAS  Google Scholar 

  17. Leroy JG, Spranger JW, Feingold M, Opitz JM, Crocker AC (1971) I-cell disease: a clinical picture. J Pediatr 79: 360–365

    CAS  PubMed  Google Scholar 

  18. Loughead JL, Mughal Z, Mimouni F, Tsang RC, Oestreich AE (1990) Spectrum and natural history of congenital hyperparathyroidism secondary to maternal hypocalcemia. Am J Perinatol 7: 350–355

    CAS  PubMed  Google Scholar 

  19. Miller SF, Proud VK, Werner AL, Field FM, Wilcox WF, Lachman RS, Rimoin DL (2003) Pacman dysplasia :a lethal skeletal dysplasia with variable radiographic features. Pediatr Radiol 33: 256–260

    Article  PubMed  Google Scholar 

  20. Okada S, Owada M, Sakiyama T, Yutaka T, Ogawa M (1985) I-cell disease: clinical studies of 21 Japanese cases. Clin Genet 28: 207–215

    CAS  PubMed  Google Scholar 

  21. Patriquin HB, Kaplan P, Kind HP, Giedion A (1977) Neonatal mucolipidosis II (I-cell disease): clinical and radiologic features in three cases. Am J Roentgenol 129: 37–43

    CAS  Google Scholar 

  22. Pazzaglia UE, Beluffi G, Danesino C, Frediani PV, Pagani G, Zatti G (1989) Neonatal mucolipidosis II. The spontaneous evolution of early bone lesions and the effect of vitamin D treatment. Pediatr Radiol 20: 80–84

    CAS  PubMed  Google Scholar 

  23. Pazzaglia UE, Beluffi Campbell JB, Bianchi E, Colavita N, Diard F, Gugliantini P, Hirche U, Kozlowski K, Marchi A, Nayanar V, Pagani G (1989) Mucolpidosis II: correlation between radiological features and histopathology of the bones. Pediatr Radiol 19: 406–413

    CAS  PubMed  Google Scholar 

  24. Pazzaglia UE, Beluffi G, Castello A, Coci A, Zatti G (1992) Bone changes of mucolipidosis II at different ages. Clin Orthop 276: 283–290

    PubMed  Google Scholar 

  25. Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG (1993) Mutations in human calcium-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297–1303

    PubMed  Google Scholar 

  26. Rapola J, Aula P (1977) Morphology of the placenta in fetal I-cell disease. Clin Genet 11: 107–113

    CAS  PubMed  Google Scholar 

  27. Reitman ML, Kornfeld S (1981) Lysosomal enzyme targeting. N-acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes. J Biol Chem 256: 11977–11980

    CAS  PubMed  Google Scholar 

  28. Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH (2000) Perinatal metabolism of vitamin D. Am J Clin Nutr 71[Suppl]:1317S–1324S

  29. Saul R, Proud V, Taylor H, Leroy J, Spranger J (2004) Pacman dysplasia is a prenatal form of mucolipidosis type II (I-cell disease). Am J Hum Genet 75[Suppl]: 652

  30. Shohat M, Rimoin DL, Gruber HE, Lachman RS (1993) New epiphyseal stippling syndrome with osteoclastic hyperplasia. Am J Med Genet 45: 558–561

    CAS  PubMed  Google Scholar 

  31. Sprigz RA, Doughty RA, Spackman TJ, Murane MJ, Coates PM, Koldovsky O, Zackai EH (1978) Neonatal presentation of I-cell disease. J Pediatr 93: 954–958

    CAS  PubMed  Google Scholar 

  32. Whelan DT, Chang PL, Cockshott PW (1983) Mucolipidosis II. The clinical, radiological and biochemical features in three cases. Clin Genet 24: 90–96

    CAS  PubMed  Google Scholar 

  33. Wilcox WR, Lucas BC, Loebel B, Bachman RP, Lachman RS, Rimoin DL (1998) Pacman dysplasia: report of two affected sibs. Am J Med Genet 77: 272–276

    CAS  PubMed  Google Scholar 

  34. Yashiro N, Abe T (1985) Radiological features of neonatal mucolipidosis II (I-cell disease): a case report. Radiat Med 3: 95–98

    CAS  PubMed  Google Scholar 

Download references


We would like to thank the families for their gracious participation in this project. David Cole is supported in part by grants from NSERC and Dairy Farmers of Canada. Andrea Superti-Furga is supported by the Swiss National Foundation (grant no. 3100A0-100485).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Sheila Unger.

Additional information

Some material from this paper was presented at the 6th International Skeletal Dysplasia Conference in Warrenton, Virginia, August 22, 2003.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Unger, S., Paul, D.A., Nino, M.C. et al. Mucolipidosis II presenting as severe neonatal hyperparathyroidism. Eur J Pediatr 164, 236–243 (2005).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Hyperparathyroidism
  • I-cell disease
  • Mucolipidosis II
  • Neonatal