Abstract
Background: Parathyroid and thymic anomalies related to embryonic neural crest dysfunction have
been demonstrated in rats with congenital diaphragmatic hernia (CDH). These rats,
like infants with CDH, have conotruncal, facial, and other neurocristal defects. The
present study examines whether parafollicular C-cells (CC) of the thyroid, whose embryogenesis
is related to that of the parathyroids and thymus, might also be abnormal in babies
with CDH.
Material and methods: Autopsy sections of the thyroids of 12 babies dead from CDH and of 11 controls were
stained with anti-calcitonin antibodies. Calcitonin-stained areas and the histological
distribution of CC within the thyroid gland were assessed. Mann-Whitney tests were
used for comparison, with p<0.05 considered significant.
Results: The proportion of stained surface to total thyroid surface was significantly smaller
in CDH babies than in controls (0.035±0.030% vs. 0.072±0.052%, p<0.05). A normal central
CC location was demonstrated in both groups.
Conclusions: Parafollicular thyroid C-cells are deficient in patients with CDH. These findings
further support the involvement of neural crest dysregulation in the pathogenesis
of CDH and the pertinence of using this experimental model to investigate the human
condition. The clinical effects of this anomaly are unknown and probably irrelevant,
but they are currently under scrutiny.
Key words
thyroid - calcitonin - C-cell - congenital diaphragmatic hernia - human
References
- 1
Migliazza L, Otten C, Xia H. et al .
Cardiovascular malformations in congenital diaphragmatic hernia: human and experimental
studies.
J Pediatr Surg.
1999;
34
1352-1358
- 2
Tovar JA, Stephen L.
Gans Distinguished Overseas Lecture. The neural crest in pediatric surgery.
J Pediatr Surg.
2007;
42
915-926
- 3
Martinez L, Pederiva F, Martinez-Calonge W. et al .
The myenteric plexus of the esophagus is abnormal in an experimental congenital diaphragmatic
hernia model.
Eur J Pediatr Surg.
2009;
19
163-167
- 4
Pederiva F, Aras Lopez R, Martinez L. et al .
Abnormal development of tracheal innervation in rats with experimental diaphragmatic
hernia.
Pediatr Surg Int.
2008;
24
1341-1346
- 5
Pederiva F, Lopez RA, Martinez L. et al .
Tracheal innervation is abnormal in rats with experimental congenital diaphragmatic
hernia.
J Pediatr Surg.
2009;
44
1159-1164
- 6
Acosta JM, Chai Y, Meara JG. et al .
Prenatal exposure to nitrofen induces Fryns phenotype in mice.
Ann Plast Surg.
2001;
46
635-640
- 7
Pederiva F, Rodriguez JI, Ruiz-Bravo E. et al .
Abnormal intrinsic esophageal innervation in congenital diaphragmatic hernia: a likely
cause of motor dysfunction.
J Pediatr Surg.
2009;
44
496-499
- 8
Yu J, Gonzalez S, Rodriguez JI. et al .
Neural crest-derived defects in experimental congenital diaphragmatic hernia.
Pediatr Surg Int.
2001;
17
294-298
- 9
Martinez L, De Ceano-Vivas M, Gonzalez-Reyes S. et al .
Las células C tiroideas están disminuidas en la hernia diafragmática experimental.
Cir Pediatr.
2006;
19
101-105
- 10
Gamallo C, Garcia M, Palacios J. et al .
Decrease in calcitonin-containing cells in truncus arteriosus.
Am J Med Genet.
1993;
46
149-153
- 11
Palacios J, Gamallo C, Garcia M. et al .
Decrease in thyrocalcitonin-containing cells and analysis of other congenital anomalies
in 11 patients with DiGeorge anomaly.
Am J Med Genet.
1993;
46
641-646
- 12
Greer JJ, Babiuk RP, Thebaud B.
Etiology of congenital diaphragmatic hernia: the retinoid hypothesis.
Pediatr Res.
2003;
53
726-730
- 13
Kling DE, Schnitzer JJ.
Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic
hernia (CDH).
Am J Med Genet C Semin Med Genet.
2007;
145C
139-157
- 14
Andersen DH.
Effect of diet during pregnancy upon the incidence of congenital hereditary diaphragmatic
hernia in the rat; failure to produce cystic fibrosis of the pancreas by maternal
vitamin A deficiency.
Am J Pathol.
1949;
25
163-185
- 15
Warkany J.
Disturbance of embryonic development by maternal vitamin deficiencies.
J Cell Physiol Suppl.
1954;
43
207-236
- 16
Thebaud B, Tibboel D, Rambaud C. et al .
Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic
hernia in rats.
Am J Physiol.
1999;
277
L423-L429
- 17
Lohnes D, Mark M, Mendelsohn C. et al .
Function of the retinoic acid receptors (RARs) during development (I). Craniofacial
and skeletal abnormalities in RAR double mutants.
Development.
1994;
120
2723-2748
- 18
Mendelsohn C, Lohnes D, Decimo D. et al .
Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities
at various stages of organogenesis in RAR double mutants.
Development.
1994;
120
2749-2771
- 19
Major D, Cadenas M, Fournier L. et al .
Retinol status of newborn infants with congenital diaphragmatic hernia.
Pediatr Surg Int.
1998;
13
547-549
- 20
Nakazawa N, Montedonico S, Takayasu H. et al .
Disturbance of retinol transportation causes nitrofen-induced hypoplastic lung.
J Pediatr Surg.
2007;
42
345-349
- 21
Nakazawa N, Takayasu H, Montedonico S. et al .
Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung.
Pediatr Surg Int.
2007;
23
391-396
- 22
Chen MH, MacGowan A, Ward S. et al .
The activation of the retinoic acid response element is inhibited in an animal model
of congenital diaphragmatic hernia.
Biol Neonate.
2003;
83
157-161
- 23
Mey J, Babiuk RP, Clugston R. et al .
Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic
hernias in rodents.
Am J Pathol.
2003;
162
673-679
- 24
Montedonico S, Nakazawa N, Puri P.
Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung
explants.
Pediatr Surg Int.
2006;
22
2-8
- 25
Noble BR, Babiuk RP, Clugston RD. et al .
Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen.
Am J Physiol Lung Cell Mol Physiol.
2007;
293
L1079-L1087
- 26
Keijzer R, Liu J, Deimling J. et al .
Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital
diaphragmatic hernia.
Am J Pathol.
2000;
156
1299-1306
- 27
Trainor PA, Krumlauf R.
Hox genes, neural crest cells and branchial arch patterning.
Curr Opin Cell Biol.
2001;
13
698-705
- 28
Manley NR, Capecchi MR.
The role of Hoxa-3 in mouse thymus and thyroid development.
Development.
1995;
121
1989-2003
- 29
Manley NR, Capecchi MR.
Hox group 3 paralogs regulate the development and migration of the thymus, thyroid,
and parathyroid glands.
Dev Biol.
1998;
195
1-15
- 30
Kim C, Nielsen HC.
Hoxa-5 in mouse developing lung: cell-specific expression and retinoic acid regulation.
Am J Physiol Lung Cell Mol Physiol.
2000;
279
L863-L871
- 31
Fu M, Chi Hang Lui V, Har Sham M. et al .
HOXB5 expression is spatially and temporarily regulated in human embryonic gut during
neural crest cell colonization and differentiation of enteric neuroblasts.
Dev Dyn.
2003;
228
1-10
- 32
Chinoy MR, Nielsen HC, Volpe MV.
Mesenchymal nuclear transcription factors in nitrofen-induced hypoplastic lung.
J Surg Res.
2002;
108
203-211
- 33
Martinez L, Ceano-Vivas MD, Gonzalez-Reyes S. et al .
Decrease of parafollicular thyroid C-cells in experimental esophageal atresia: further
evidence of a neural crest pathogenic pathway.
Pediatr Surg Int.
2005;
21
175-179
Correspondence
Leopoldo MartinezMD
Hospital Infantil La Paz
Pediatric Surgery
Paseo de la Castellana 261
28046 Madrid
Spain
Phone: +34 91 727 70 19
Fax: +34 91 727 74 78
Email: lmartinezm.hulp@salud.madrid.org