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Association of DiGeorge anomaly and caudal dysplasia sequence in a neonate born to a diabetic mother

Published online by Cambridge University Press:  06 March 2012

Maria L. Dentici ,
Silvia Placidi ,
Paola Francalanci ,
Rossella Capolino ,
Gabriele Rinelli ,
Bruno Marino ,
Maria C. Digilio  and
Bruno Dallapiccola
Maria L. Dentici
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
Silvia Placidi
Affiliation:
Department of Pediatric Cardiology, University “La Sapienza”, Rome, Italy
Paola Francalanci
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
Rossella Capolino
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
Gabriele Rinelli
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
Bruno Marino
Affiliation:
Department of Pediatric Cardiology, University “La Sapienza”, Rome, Italy
Maria C. Digilio*
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
Bruno Dallapiccola
Affiliation:
Department of Medical Genetics, Cardiology and Pathology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
*
Correspondence to: M. C. Digilio, MD, Department of Medical Genetics, Bambino Gesù Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy. Tel: +39 06 68592227; Fax: +39 06 68592004; E-mail: mcristina.digilio@opbg.net
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Abstract

Aim/objective

Several studies have demonstrated a significantly increased risk of specific patterns of congenital anomalies in infants born to diabetic mothers. In particular, caudal dysplasia sequence has been linked to pregnancy complicated by maternal diabetes. In addition, several cases of infants born to diabetic mothers presenting with features of DiGeorge anomaly have been reported. Infants with DiGeorge anomaly can display additional manifestations within the spectrum of caudal dysplasia sequence, including vertebral anomalies and renal agenesis.

Methods

We report a neonate presenting with the co-occurrence of features of both DiGeorge anomaly and caudal dysplasia sequence, born to a mother with poorly controlled insulin-dependent diabetes.

Results

The patient was affected by truncus arteriosus type A1 and hypertrophic cardiomyopathy.

Conclusion

Maternal diabetes can cause a spectrum of manifestations, expressing with isolated DiGeorge anomaly or caudal dysplasia sequence, with intermediate phenotypes or with the co-occurrence of both the congenital anomalies in the same patient. The present observations argue for a feasible link between truncus arteriosus with hypertrophic cardiomiopathy, DiGeorge anomaly, and maternal diabetes.

Keywords

Insulin-dependent diabetessacral regressionconotruncal malformationcongenital heart defect

Information

Type
Original Article
Information
Cardiology in the Young , Volume 23 , Issue 1 , February 2013 , pp. 14 - 17
Copyright
Copyright © Cambridge University Press 2012

Studies of infants of diabetic mothers have demonstrated a two- to sixfold increased risk of congenital anomalies,Reference Becerra, Khoury, Cordero and Erickson 1 with specific patterns of malformations, such as holoprosencephaly, renal/urinary defects, vertebral/rib defects, and laterality defects that occur more often in infants of diabetic mothers than in infants born to non-diabetic mothers.Reference Kucera 2 – Reference Martinez-Frias, Bermejo, Rodriguez-Pinilla, Prieto and Frias 4 The Baltimore-Washington Infant Study has reported an increased risk of cardiac anomalies in infants of diabetic mothers, including outflow tract anomalies, laterality defects, and cardiomyopathy.Reference Loffredo, Wilson and Ferencz 5 Considering specific malformation syndromes, caudal dysplasia sequence has shown a distinct link with maternal diabetes.Reference Passarge and Lenz 6 In addition, several cases of infants of diabetic mothers presenting with the features of DiGeorge anomalyReference Gosseye, Golaire, Verellen, van Lierde and Claus 7 – Reference Kumar, Sapire, Lockhart, McCombs, Hawkins and Van Mierop 11 and of oculo-auriculo-vertebral spectrumReference Wang, Martinez-Frias and Graham 12 have been reported. Infants with DiGeorge anomaly born from diabetic mothers can also display clinical manifestations that are part of the caudal dysplasia sequence spectrum, including vertebral/renal anomalies or club feet.Reference Gosseye, Golaire, Verellen, van Lierde and Claus 7 On the other hand, finding DiGeorge anomaly features in a series of patients reviewed as caudal dysplasia sequence seems rare.Reference Bohring, Lewin and Reynolds 13

We have previously reported infants of diabetic mothers with clinical characteristics of DiGeorge anomaly associated with renal agenesis, but lacking skeletal defects of the caudal region, which is generally found in caudal dysplasia sequence.Reference Digilio, Marino, Formigari and Giannotti 10 Among the present personal series of 204 patients with DiGeorge anomaly/Velo-cardio-facial syndrome (OMIM 192430) and nine patients with caudal dysplasia sequence, evaluated between January 1992 and May 2011, we observed a neonate, born to a mother with poorly controlled insulin-dependent diabetes, in whom features of DiGeorge anomaly and caudal dysplasia sequence were coexisting.

Clinical report

The proband, a female, was the first child of a mother affected by insulin-dependent diabetes since the age of 14 years. Family history was otherwise unremarkable, and consanguinity was denied. The baby was born by Caesarean section at the 37th week of gestation. The pregnancy was complicated by poorly controlled blood sugars. Insulin treatment was used for glycaemic control, although the mother did not make regular use of it. Birth weight was 3980 grams (greater than 97th centile), length 46 centimetres (less than 3rd centile), and head circumference 35 centimetres (50th centile). Apgar scores were 6 and 7 at 1 and 5 minutes, respectively. Clinical examination at birth showed macrosomia, generalised oedema, smaller and uniformly hypoplastic lower limbs, and equinovarus feet deformity. No obvious facial dysmorphic features were apparent.

Two-dimensional color Doppler echocardiography showed truncus arteriosus type A1 of Van Praagh, with hypertrophic cardiomyopathy involving the left ventricle and the interventricular septum. Cerebral ultrasonography disclosed a large intracranial subependymal haemorrhage in the germinal matrix with increased vascular resistances. Bilateral hypoplastic kidneys with persistence of foetal lobulation were detected by renal ultrasound (longitudinal diameter: 36 millimetres; parenchymal average thickness: 8 millimetres). Skeletal X-ray examination showed multiple vertebral malformations in the thoracic and lumbosacral spine, with incomplete development of the sacrum, and decreased length of all lower limb bones.

Laboratory investigations showed severe hypoglycaemia (23 milligrams per decalitre) in the first days of life, insulinaemia below the normal range (4.3 microinternational units per millilitre), normal insulin growth factor-1 levels (125 nanograms per millilitre), reduced proteins, and mild hyperbilirubinaemia (total bilirubin: 1.87milligrams per decalitre; direct bilirubin: 0.17 milligrams per decalitre). Serum calcium (8.8 milligrams per decalitre) and parathyroid hormone (15 picograms per millilitre) were normal despite the absence of parathyroid glands (see autopsy). The T-cell number was below the normal range: CD3 35% (normal value 58–75%); CD4 20% (normal value 29–47%); CD8 14% (normal value 17–33%). Standard chromosome analysis on circulating lymphocytes showed a normal 46,XX karyotype. Fluorescence in situ hybridisation analysis using the LSI N25 probe specific for 22q11.2 (Vysis, Abbott Laboratories, Chicago, Illinois, United States of America) revealed an unremarkable pattern.

The patient died on the 45th day of life of cardiorespiratory insufficiency. The autopsy showed marked cerebral atrophy with cystic lesions in the frontal region, bilaterally. Heart examination showed truncus arteriosus type A1 (Fig 1a) with juxtatruncal ventricular septal defect (Fig 1b). Both ventricles displayed severe wall hypertrophy, confirming hypertrophic cardiomyopathy. Absence of the thymus and parathyroid glands was noted. Kidneys were mildly hypoplastic, lacking abnormal parenchymal differentiation.

Figure 1

(a) External appearance of truncus arteriosus type A1, anterior view. The great arteries seem almost completely divided and normally interrelated. This aspect is seen in truncus only when the aortopulmonary septum is quite well formed. (b) Truncus arteriosus from left ventricular aspect. The three leaflets truncal valve shows mild myxoid features. Note the juxtatruncal ventricular septal defect.

Discussion

Clinical features in the present patient are compatible with the co-occurrence of both DiGeorge anomaly and caudal dysplasia sequence (Table 1). DiGeorge anomaly is an aetiologically heterogeneous developmental field defect related to neural crest cells migration anomaly, clinically characterised by the association of conotruncal heart defect, hypoplasia or absence of the thymus and immune deficit, neonatal hypocalcaemia, and facial anomalies.Reference DiGeorge 14 The cardiac defects more commonly found in DiGeorge anomaly include tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch.Reference Marino, Digilio and Toscano 15 Most patients with DiGeorge anomaly have a microdeletion of chromosome 22q11.2.Reference Greenberg 16 The frequency of chromosome 22q11.2 deletion in conotruncal malformation ranges between 7% and 48%.Reference Iserin, de Lonlay and Viot 17 , Reference Ziolkowska, Kawalec and Turska-Kmiec 18 In particular, truncus arteriosus, found in our patient, occurs in 34–46% of 22q11.2 deletion patients.Reference Goldmuntz, Clark and Mitchell 19 , Reference Anilkumar, Kappanayil, Thampi, Nampoothiri, Sundaram and Vasudevan 20 DiGeorge anomaly has also been reported in several recognisable malformation patterns or in association with the exposure to different teratogens, including maternal diabetes.Reference Gosseye, Golaire, Verellen, van Lierde and Claus 7 – Reference Kumar, Sapire, Lockhart, McCombs, Hawkins and Van Mierop 11 Renal and vertebral malformations have been found in infants of diabetic mothers with DiGeorge anomaly.Reference Gosseye, Golaire, Verellen, van Lierde and Claus 7 , Reference Wilson, Blethen and Vallone 9 , Reference Digilio, Marino, Formigari and Giannotti 10 Structural defects of the caudal region are cardinal features of caudal dysplasia sequence.Reference Welch and Aterman 21 These include incomplete development of the sacrum and of the lumbar vertebrae, skeletal limb anomalies secondary to neurologic impairment, and decreased leg movements. Caudal dysplasia sequence is a rare heterogeneous congenital defect resulting from an insult to the structures of caudal eminence. Suggested aetiologic and pathogenetic mechanisms include maternal diabetes,Reference Passarge and Lenz 6 genetic predisposition,Reference Finer, Bowen and Dunbar 22 environmental teratogenic factors,Reference Padmanbhan 23 and vascular hypoperfusion.Reference Stevenson, Jones and Phelan 24 In particular, it has been estimated that 16% of human cases of sacral agenesis are associated with maternal diabetes mellitus.Reference Passarge and Lenz 6 Associated anomalies affecting other systems are often present, including cardiovascular, neurological, gastrointestinal, and genitourinary system defects.

Table 1

Clinical features of the present patient compared with the characteristics of DiGeorge anomaly and caudal dysplasia sequence.

aGreenberg, 1993

bBohring et al, 1999

The empiric risk of congenital heart defects to the offspring of insulin-dependent diabetic mothers is 18%.Reference Becerra, Khoury, Cordero and Erickson 1 The anatomic types of structural congenital heart defects observed in infants of diabetic mothers include hypertrophic cardiomyopathy,Reference Ferencz, Rubin, McCarter and Clark 8 mimicking asymmetric septal hypertrophy and conotruncal malformations, in particular truncus arteriosus and double outlet right ventricle.Reference Loffredo, Wilson and Ferencz 5 It has been speculated that diabetic women may transfer factors across the placenta to the embryo that alters the normal migration of neural crest ectomesenchymal tissue.Reference Ferencz, Rubin, McCarter and Clark 8 The diagnosis of truncus arteriosus type A1 in the present patient suggests a link between maternal diabetes, DiGeorge anomaly, and cardiac defects. The co-occurrence of congenital heart defects and hypertrophic cardiomyopathy in infants of diabetic mothers has been described previously.Reference Cheatham, McManus, Kugler and Hofshire 25 In conclusion, DiGeorge anomaly and caudal dysplasia sequence have been independently seen in association with maternal diabetes. Therefore, their co-occurrence in the present case argues for a relationship with maternal diabetes, which can cause a wide spectrum of defects, manifesting either as isolated DiGeorge anomaly or caudal dysplasia sequence, or DiGeorge anomaly associated with renal and vertebral malformations, or DiGeorge anomaly plus caudal dysplasia sequence. Truncus arteriosus with hypertrophic cardiomiopathy is likely a distinct type of congenital heart defect associated with DiGeorge anomaly or secondary to maternal diabetes.

References

1. Becerra, JE, Khoury, MJ, Cordero, JF, Erickson, JD. Diabetes mellitus during pregnancy and the risk for specific birth defects: a population-based case-control study. Pediatrics 1990; 85: 1–9.CrossRefGoogle ScholarPubMed
2. Kucera, J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971; 7: 61–70.Google Scholar
3. Martinez-Frias, ML. Epidemiological analysis of outcomes of pregnancy in diabetic mothers: identification of the most characteristic and most frequent congenital anomalies. Am J Med Genet 1994; 51: 108–113.Google Scholar
4. Martinez-Frias, ML, Bermejo, E, Rodriguez-Pinilla, E, Prieto, L, Frias, JL. Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet 1998; 78: 140–145.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
5. Loffredo, CA, Wilson, PD, Ferencz, C. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 2001; 64: 98–106.CrossRefGoogle ScholarPubMed
6. Passarge, E, Lenz, W. Syndrome of caudal regression in infants of diabetic mothers: observations of further cases. Pediatrics 1966; 37: 672–675.CrossRefGoogle ScholarPubMed
7. Gosseye, S, Golaire, MC, Verellen, G, van Lierde, M, Claus, D. Association of bilateral renal agenesis and DiGeorge syndrome in an infant of a diabetic mother. Helv Paediatr Acta 1982; 37: 471–474.Google Scholar
8. Ferencz, C, Rubin, JD, McCarter, RJ, Clark, EB. Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus. Teratology 1990; 41: 319–326.Google Scholar
9. Wilson, TA, Blethen, SL, Vallone, A, et al. DiGeorge anomaly with renal agenesis in infants of mothers with diabetes. Am J Med Genet 1993; 47: 1078–1082.Google Scholar
10. Digilio, MC, Marino, B, Formigari, R, Giannotti, A. Maternal diabetes causing DiGeorge anomaly and renal agenesis. Am J Med Genet 1995; 55: 513–514.CrossRefGoogle ScholarPubMed
11. Kumar, A, Sapire, DW, Lockhart, LH, McCombs, J, Hawkins, HK, Van Mierop, LH. Atrioventricular septal defect with pulmonary atresia in DiGeorge anomaly: expansion of the cardiac phenotype. Am J Med Genet 1996; 61: 89–91.Google Scholar
12. Wang, R, Martinez-Frias, ML, Graham, JM. Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: a case-based and case-control approach. J Pediatr 2002; 141: 611–617.CrossRefGoogle ScholarPubMed
13. Bohring, A, Lewin, SO, Reynolds, JF, et al. Polytopic anomalies with agenesis of the lower vertebral column. Am J Med Genet 1999; 87: 99–114.Google Scholar
14. DiGeorge, AM. Discussion of a new concept of the cellular basis of immunology. J Pediatr 1965; 67: 907–908.Google Scholar
15. Marino, B, Digilio, MC, Toscano, A, et al. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med 2001; 3: 45–48.Google Scholar
16. Greenberg, F. DiGeorge syndrome: an historical review of clinical and cytogenetic features. J Med Genet 1993; 30: 803–806.Google Scholar
17. Iserin, L, de Lonlay, P, Viot, G, et al. Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies. Eur J Pediatr 1998; 157: 881–884.Google Scholar
18. Ziolkowska, L, Kawalec, W, Turska-Kmiec, A. Chromosome 22q11.2 microdeletion in children with conotruncal heart defects: frequency, associated cardiovascular anomalies, and outcome following cardiac surgery. Eur J Pediatr 2008; 167: 1135–1140.CrossRefGoogle ScholarPubMed
19. Goldmuntz, E, Clark, BJ, Mitchell, LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998; 32: 492–498.CrossRefGoogle ScholarPubMed
20. Anilkumar, A, Kappanayil, M, Thampi, M, Nampoothiri, S, Sundaram, K, Vasudevan, D. Variation in prevalence of chromosome 22q11 deletion in subtypes of conotruncal defect in 254 children. Acta Paediatr 2011; 100: 97–100.Google Scholar
21. Welch, JP, Aterman, K. Syndrome of caudal regression: a review, including etiologic considerations and evidence of heterogeneity. Pediatr Pathol 1984; 2: 313–327.Google Scholar
22. Finer, NN, Bowen, P, Dunbar, LG. Caudal regression anomalad (sacral agenesis) in siblings. Clin Genet 1978; 13: 353–358.Google Scholar
23. Padmanbhan, R. Retinoic acid-induced caudal regression syndrome in the mouse fetus. Reprod Toxicol 1998; 12: 496–498.Google Scholar
24. Stevenson, RE, Jones, KL, Phelan, MC, et al. Vascular steal: the pathogenic mechanism producing sirenomelia and associated defects of the viscera and soft tissue. Pediatrics 1986; 78: 451–457.CrossRefGoogle Scholar
25. Cheatham, JP, McManus, BM, Kugler, JD, Hofshire, PJ. Hypoplastic left heart syndrome in an infant of diabetic mother: two-dimensional, pulsed Doppler, and contrast echocardiographic diagnosis. J Cardiovasc Ultrasound 1988; 7: 9–13.Google Scholar
Figure 0

Figure 1 (a) External appearance of truncus arteriosus type A1, anterior view. The great arteries seem almost completely divided and normally interrelated. This aspect is seen in truncus only when the aortopulmonary septum is quite well formed. (b) Truncus arteriosus from left ventricular aspect. The three leaflets truncal valve shows mild myxoid features. Note the juxtatruncal ventricular septal defect.

Figure 1

Table 1 Clinical features of the present patient compared with the characteristics of DiGeorge anomaly and caudal dysplasia sequence.