Multiple signaling and metabolic pathways are involved in fetal bone development, and the identification of human mutations has served as a major guide for
uncovering these signaling pathways and mechanisms.
Although genetically related dysregulation of these path
ways can eventually lead to human skeletal diseases, many of them are difficult to diagnose in newborns. This is because the milder spectrum of diseases may not cause pronounced deformity of the skeleton, and the clinical consequences of abnormal bone mass, such as fracture, may not be evident given the relatively mild mechanical loading in the fetal or neonatal stages. Here, we have selected several examples of severe bone diseases that underscore key developmental processes affecting fetal and neonatal bone development to review.
Defects in bone matrix production
OI is a group of inborn bone diseases in humans charac
terized by brittle bone. The most severe forms of OI can lead to bone fractures and lethality in fetuses and neo
nates. Etiologies of these severe OIs are related to abnor
mal production, posttranslational modification, or metabolism of fibrillar collagens, especially type I colla
gen, which are the major content of bone matrix pro
duced from osteoblast lineage. For example, dominantly inherited point mutations in COL1A1 and COL1A2, encoding the proa1(I) and proa2(I) chains of type I colla
gen, lead to posttranslational overmodification of colla
gen chains and severe forms of OI (types II and III) [33].
More recently described recessive mutations in genes important for modification or trafficking of type I colla
gen also cause OI. The expanding list of OI‐related genes (and the corresponding gene products) includes CRTAP (cartilage associated protein) [34], LEPRE1 (prolyl 3 hydroxylase 1) [35], PPIB (cyclophilin B) [36], FKBP10 (FK506 binding protein 10) [37], SERPINH1 (heat shock protein 47) [38] and SERPINF1 (pigment epithelial derived factor) [39], BMP1(bone morphogenetic protein‐1/Tolloid) [40], WNT1 (MMTV integration site 1) [41], etc.
Defects in mineral homeostasis
Recessive inactivating mutations of the calcium sensing receptor gene (CASR) are the cause of neonatal severe pri
mary hyperparathyroidism (NSHPT) [42,43]. This disease is characterized by extreme hypercalcemia and severe neona
tal hyperparathyroidism, including demineralization of the skeleton, respiratory distress and parathyroid hyperplasia.
Without prompt parathyroidectomy of the affected infants, NSHPT is usually lethal. In contrast, familial hypocalciuric hypercalcemia (FHH), caused by haploinsufficiency of CASR, affords a much milder hypocalcemia and does not exhibit the complexity of hyperparathyroidism.
Defects in mineral deposition
Perinatal and infantile hypophosphatasia is a pernicious inborn metabolic disease manifesting in utero with profound hypomineralization that results in caput
120 Human Fetal and Neonatal Bone Development membraneceum, deformed or shortened limbs, and rapid death due to respiratory failure. Infantile hypophosphata
sia is caused by recessive mutations in the gene encoding tissue‐nonspecific isoenzyme of alkaline phosphatase (TNSALP), a glycoprotein localized to the plasma mem
branes of osteoblasts and chondrocytes that hydrolyzes monophosphate esters at an alkaline pH optimum [44].
The deficiency of TSNALP activity leads to extracellular accumulation of inorganic pyrophosphate (PPi) which potently inhibits growth of hydroxyapatite crystal and causes severe hypomineralization in the infant’s bone [45]. Haploinsufficiency of TNSALP also causes hypophos
phatasia, but in a milder manner, usually diagnosed later in life.
Defects in osteoclastic function
Infantile malignant osteopetrosis (IMO) is a group of severe autosomal recessive osteopetrosis. The affected bones become very brittle, although bone mass is markedly higher than normal. IMO arises in the fetal stage, thus fractures of the clavicle can be found during delivery and frequent bone fractures occur during infancy.
The affected infants suffer from hypocalcemia. Moreover, due to defective osteoclastic function, the bone marrow space, which accommodates hematopoiesis, is gradually diminished. Hence, if not properly treated in the first year, most affected infants develop anemia and thrombo
cytopenia because of encroachment of bone on marrow [46]. Genetically, IMO is caused by mutations in the genes important for osteoclast activity. The bone resorp
tion of osteoclasts primarily relies on the acidification of bone resorption lacunae. Hence, defects in the machinery for acid secretion, such as that caused by mutations in either CLCN7 or OSTM1 (CLCN7 encodes the chloride channel 7 which complexes with and is stabilized by the OSTM1 gene product, the osteopetrosis‐associated transmembrane protein 1) or in TRCIRG1 (encoding T cell immune regulator 1, a subunit of a vacuolar proton pump) have been identified in the osteoclast‐rich IMO patients [47–50].
Defects in cranial suture closure and osteogenesis
The skull of neonates is composed of separate cranial bones connected by fibrous cranial sutures (fontanels).
These sutures provide flexibility for the skull to facilitate its passage through the birth canal without damaging the infant’s brain. Moreover, cranial sutures contain osteo
genic mesenchymal cells, serving as important sites for cranial bone growth to adapt to the rapid brain growth of infancy [51,52]. The fusion of cranial bones normally starts after infancy and completes by adulthood. Disorders char
acterized by delayed or premature closure of cranial sutures are not rare in newborns. Cleidocranial dysplasia (CCD) patients have persistently open and unossified skull
sutures. This is caused by a haploinsufficiency of Runx2, a master gene that regulates multiple steps of osteoblast differentiation [53–55]. In contrast, premature suture clo
sure leads to craniosynostosis, which can severely restrain growth of the skull, thus leading to increased intracranial pressure that can severely impair neural development [51].
The etiologies of craniosynostosis include dominant acti
vating mutations in the FGF receptors (FGFR1, 2 and 3) [56–59] or haploinsufficiency of TWIST1 [60,61]. Mutations in MSX2 [62], EFNB1 [63], Gli3 [64], RAB23 [65], POR [66], and RECQL4 [67] have also been identified in some rare types of craniosynostosis.
SUMMARY
Overall, fetal and neonatal bone development is a dynamic and complicated process orchestrated by multi
ple intrinsic or extrinsic factors. Mutations in the genes important for skeletal cell differentiation and function, or for extracellular matrix production, modifications, and mineralization, can cause dramatic abnormality of the fetal/neonatal skeleton. Moreover, fetal/neonatal bone development is greatly influenced by maternal nutrition and health, hormones, toxins, and in utero environment.
Accumulating data suggest that aside from affecting fetal bone development, the exposure to these external factors in early life can epigenetically influence postnatal bone homeostasis. This underscores that better understanding of the physiological processes of early bone development may also help optimize bone health throughout life.
REFERENCES
1. Salle BL, Rauch F, Travers R, et al. Human fetal bone development: histomorphometric evaluation of the prox
imal femoral metaphysis. Bone. 2002;30(6):823–8.
2. Gardner E. Osteogenesis in the Human Embryo and Fetus.
Development and Growth. Elsevier BV, 1971, p. 77–118.
3. Blumer MJ, Schwarzer C, Perez MT, et al. Identification and location of bone‐forming cells within cartilage canals on their course into the secondary ossification centre.
J Anat. 2006;208(6):695–707.
4. Burkus JK, Ganey TM, Ogden JA. Development of the cartilage canals and the secondary center of ossification in the distal chondroepiphysis of the prenatal human femur. Yale J Biol Med. 1993;66(3):193–202.
5. Zoetis T, Tassinari MS, Bagi C, et al. Species comparison of postnatal bone growth and development. Birth Defects Res B Dev Reprod Toxicol. 2003;68(2):86–110.
6. Neer R, Berman M, Fisher L, et al. Multicompartmental Analysis of Calcium Kinetics in Normal Adult Males.
J Clin Invest. 1967;46(8):1364–79.
7. Bianco SDC, Peng J‐B, Takanaga H, et al. Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene.
J Bone Miner Res. 2006;22(2):274–85.
8. Belkacemi L, Bédard I, Simoneau L, et al. Calcium channels, transporters and exchangers in placenta: a review. Cell Calcium. 2005;37(1):1–8.
9. Suzuki Y, Kovacs CS, Takanaga H, et al. Calcium Channel TRPV6 Is Involved in Murine Maternal‐Fetal Calcium Transport. J Bone Miner Res. 2008;23(8):1249–56.
10. Shibasaki Y, Etoh N, Hayasaka M, et al. Targeted dele
tion of the tybe IIb Na+‐dependent Pi‐co‐transporter, NaPi‐IIb, results in early embryonic lethality. Biochem Biophys Res Commun. 2009;381(4):482–6.
11. Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phos
photropic hormones. Physiol Rev. 2014;94(4):1143–218.
12. Kovacs CS, Lanske B, Hunzelman JL, et al. Parathyroid hormone‐related peptide (PTHrP) regulates fetal‐placen
tal calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci U S A.
1996;93(26):15233–8.
13. Salle BL, Glorieux FH, Delvin EE. Perinatal Vitamin D Metabolism. Biol Neonate. 1988;54(4):181–7.
14. Mahon P, Harvey N, Crozier S, et al. Low maternal vita
min D status and fetal bone development: Cohort study.
J Bone Miner Res. 2009;25(1):14–9.
15. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–8.
16. Zhu K, Whitehouse AJ, Hart PH, et al. Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study. J Bone Miner Res. 2014;29(5):1088–95.
17. Lieben L, Stockmans I, Moermans K, et al. Maternal hypervitaminosis D reduces fetal bone mass and min
eral acquisition and leads to neonatal lethality. Bone.
2013;57(1):123–31.
18. McDonald KR, Fudge NJ, Woodrow JP, et al. Ablation of calcitonin/calcitonin gene‐related peptide‐alpha impairs fetal magnesium but not calcium homeostasis. Am J Physiol Endocrinol Metab. 2004;287(2):E218–26.
19. Dennison EM, Syddall HE, Rodriguez S, et al.
Polymorphism in the growth hormone gene, weight in infancy, and adult bone mass. J Clin Endocrinol Metab.
2004;89(10):4898–903.
20. Heppe DH, Medina‐Gomez C, Hofman A, et al. Maternal first‐trimester diet and childhood bone mass: the Generation R Study. Am J Clin Nutr. 2013;98(1):
224–32.
21. Godfrey K, Walker‐Bone K, Robinson S, et al. Neonatal Bone Mass: Influence of Parental Birthweight, Maternal Smoking, Body Composition, and Activity During Pregnancy. J Bone Miner Res. 2001;16(9):1694–703.
22. Dennison EM, Arden NK, Keen RW, et al. Birthweight, vitamin D receptor genotype and the programming of osteoporosis. Paediatr Perinat Epidemiol. 2001;15(3):
211–9.
23. Land C, Schoenau E. Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition. Best Pract Res Clin Endocrinol Metab.
2008;22(1):107–18.
24. Rauch F, Schoenau E. Changes in Bone Density During Childhood and Adolescence: An Approach Based on Bone’s Biological Organization. J Bone Miner Res.
2001;16(4):597–604.
25. Alexander PG, Tuan RS. Role of environmental factors in axial skeletal dysmorphogenesis. Birth Defects Res C Embryo Today. 2010;90(2):118–32.
26. Husain SM, Birdsey TJ, Glazier JD, et al. Effect of Diabetes Mellitus on Maternofetal Flux of Calcium and Magnesium and Calbindin9K mRNA Expression in Rat Placenta. Pediatr Res. 1994;35(3):376–80.
27. Namgung R, Tsang RC. Factors affecting newborn bone mineral content: in utero effects on newborn bone min
eralization. Proc Nutr Soc. 2000;59(01):55–63.
28. Ferreira JC, Choufani S, Grafodatskaya D, et al. WNT2 pro
moter methylation in human placenta is associated with low birthweight percentile in the neonate. Epigenetics.
2011;6(4):440–9.
29. Cooper C, Fall C, Egger P, et al. Growth in infancy and bone mass in later life. Ann Rheum Dis. 1997;56(1):
17–21.
30. Javaid MK, Lekamwasam S, Clark J, et al. Infant growth influences proximal femoral geometry in adulthood.
J Bone Miner Res. 2006;21(4):508–12.
31. Cooper C, Eriksson JG, Forsen T, et al. Maternal height, childhood growth and risk of hip fracture in later life:
a longitudinal study. Osteoporosis Int. 2001;12(8):
623–9.
32. Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A.
2008;105(44):17046–9.
33. Marini JC, Forlino A, Cabral WA, et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteogly
cans. Hum Mutat. 2007;28(3):209–21.
34. Morello R, Bertin TK, Chen Y, et al. CRTAP Is Required for Prolyl 3‐ Hydroxylation and Mutations Cause Recessive Osteogenesis Imperfecta. Cell. 2006;127(2):
291–304.
35. Cabral WA, Chang W, Barnes AM, et al. Prolyl 3‐ hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007;39(3):359–65.
36. van Dijk FS, Nesbitt IM, Zwikstra EH, et al. PPIB Mutations Cause Severe Osteogenesis Imperfecta. Am J Hum Genet. 2009;85(4):521–7.
37. Alanay Y, Avaygan H, Camacho N, et al. Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal‐Recessive Osteogenesis Imperfecta. Am J Hum Genet. 2010;86(4):551–9.
38. Christiansen HE, Schwarze U, Pyott SM, et al.
Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta.
Am J Hum Genet. 2010;86(3):389–98.
39. Becker J, Semler O, Gilissen C, et al. Exome Sequencing Identifies Truncating Mutations in Human SERPINF1
122 Human Fetal and Neonatal Bone Development in Autosomal‐Recessive Osteogenesis Imperfecta. Am J Hum Genet. 2011;88(3):362–71.
40. Asharani PV, Keupp K, Semler O, et al. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet. 2012;90(4):661–74.
41. Laine CM, Joeng KS, Campeau PM, et al. WNT1 mutations in early‐onset osteoporosis and osteo
genesis imperfecta. N Engl J Med. 2013;368(19):
1809–16.
42. Bai M, Pearce SH, Kifor O, et al. In vivo and in vitro char
acterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+‐
sensing receptor gene: normal maternal calcium homeo
stasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest. 1997;99(1):88–96.
43. Pollak MR, Brown EM, Chou Y‐HW, et al. Mutations in the human Ca2+‐sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyper
parathyroidism. Cell. 1993;75(7):1297–303.
44. Weiss MJ, Cole DE, Ray K, et al. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci U S A. 1988;85(20):7666–9.
45. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci.
2010;1192(1):190–200.
46. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009;4(1):5.
47. Lange PF, Wartosch L, Jentsch TJ, et al. ClC‐7 requires Ostm1 as a β‐subunit to support bone resorption and lysosomal function. Nature. 2006;440(7081):220–3.
48. Vezzoni P, Frattini A, Orchard PJ, et al. Nat Genet.
2000;25(3):343–6.
49. Kornak U, Kasper D, Bösl MR, et al. Loss of the ClC‐7 Chloride Channel Leads to Osteopetrosis in Mice and Man. Cell. 2001;104(2):205–15.
50. Ramírez A, Faupel J, Goebel I, et al. Identification of a novel mutation in the coding region of the grey‐lethal gene OSTM1 in human malignant infantile osteopetro
sis. Hum Mutat. 2004;23(5):471–6.
51. Morriss‐Kay GM, Wilkie AOM. Growth of the normal skull vault and its alteration in craniosynostosis:
insights from human genetics and experimental studies.
J Anat. 2005;207(5):637–53.
52. Opperman LA. Cranial sutures as intramembranous bone growth sites. Dev Dyn. 2000;219(4):472–85.
53. Mundlos S, Otto F, Mundlos C, et al. Mutations Involving the Transcription Factor CBFA1 Cause Cleidocranial Dysplasia. Cell. 1997;89(5):773–9.
54. Lee B, Thirunavukkarasu K, Zhou L, et al. Missense mutations abolishing DNA binding of the osteoblast‐
specific transcription factor OSF2/CBFA1 in cleidocra
nial dysplasia. Nat Genet. 1997;16(3):307–10.
55. Otto F, Thornell AP, Crompton T, et al. Cbfa1, a Candidate Gene for Cleidocranial Dysplasia Syndrome, Is Essential for Osteoblast Differentiation and Bone Development. Cell. 1997;89(5):765–71.
56. Muenke M, Schell U, Hehr A, et al. A common muta
tion in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. 1994;8(3):269–74.
57. Meyers GA, Orlow SJ, Munro IR, et al. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans.
Nat Genet. 1995;11(4):462–4.
58. Rutland P, Pulleyn LJ, Reardon W, et al. Identical muta
tions in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. 1995;9(2):173–6.
59. Bellus GA, Gaudenz K, Zackai EH, et al. Identical muta
tions in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syn
dromes. Nat Genet. 1996;14(2):174–6.
60. Howard TD, Paznekas WA, Green ED, et al. Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre‐Chotzen syndrome. Nat Genet. 1997;15(1):36–41.
61. Ghouzzi VE, Merrer ML, Perrin‐Schmitt F, et al.
Mutations of the TWIST gene in the Saethre‐Chotzene syndrome. Nat Genet. 1997;15(1):42–6.
62. Jabs EW, Müller U, Li X, et al. A mutation in the homeo
domain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell.
1993;75(3):443–50.
63. Wieland I, Jakubiczka S, Muschke P, et al. Mutations of the Ephrin‐B1 Gene Cause Craniofrontonasal Syndrome.
Am J Hum Genet. 2004;74(6):1209–15.
64. Vortkamp A, Gessler M, Grzeschik K‐H. GLI3 zinc‐
finger gene interrupted by translocations in Greig syn
drome families. Nature. 1991;352(6335):539–40.
65. Jenkins D, Seelow D, Jehee FS, et al. RAB23 Mutations in Carpenter Syndrome Imply an Unexpected Role for Hedgehog Signaling in Cranial‐Suture Development and Obesity. Am J Hum Genet. 2007;80(6):1162–70.
66. Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxi
doreductase causes disordered steroidogenesis with and without Antley‐Bixler syndrome. Nat Genet. 2004;36(3):
228–30.
67. Mendoza‐Londono R, Lammer E, Watson R, et al.
Characterization of a New Syndrome That Associates Craniosynostosis, Delayed Fontanel Closure, Parietal Foramina, Imperforate Anus, and Skin Eruption:
CDAGS. Am J Hum Genet. 2005;77(1):161–8.
123
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. Edited by John P. Bilezikian.
© 2019 American Society for Bone and Mineral Research. Published 2019 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/asbmrprimer