oculoauriculovertebral abnormalities in children of diabetic mothers
TRANSCRIPT
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Oculoauriculovertebral Abnormalities in Childrenof Diabetic Mothers
Amanda Ewart-Toland,1 Jerome Yankowitz,2 Alison Winder,1 Robin Imagire,3 Victoria A. Cox,1Arthur S. Aylsworth,4 and Mahin Golabi1*1Department of Pediatrics, University of California, San Francisco, California2Department of Obstetrics and Gynecology, University of Iowa Hospitals & Clinics, Iowa City, Iowa3Department of Medical Genetics, Kaiser Permanente, Sacramento, California4Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina
Maternal diabetes is known to have terato-genic effects. Malformations including neu-ral tube defects, caudal dysgenesis, verte-bral defects, congenital heart defects,femoral hypoplasia, and renal anomaliesare described in infants of diabetic mothers.However, craniofacial anomalies haverarely been reported in such infants. Herewe document craniofacial anomalies of pa-tients born to diabetic mothers. We describetwo patient populations: individuals evalu-ated through our genetics services for mul-tiple malformations and individuals identi-fied through a database search in ourcraniofacial clinic. The first group consistsof 14 individuals evaluated in our geneticsclinics who were born to diabetic mothersand had craniofacial anomalies. The secondgroup consists of seven individuals whowere identified from a craniofacial databasesearch of patients with hemifacial microso-mia and who were born to diabetic mothers.Thus, both groups were born to diabeticmothers and had hemifacial microsomia(67%), microtia (52%), hearing loss (43%),epibulbar dermoids (24%), and fused cervi-cal vertebrae (24%). Therefore, the terato-genic effects of maternal diabetes probablyinclude such craniofacial malformations asthe oculoauriculovertebral/Goldenhar com-plex. Infants of diabetic mothers should beevaluated for craniofacial anomalies. Con-versely, mothers of infants with craniofacialanomalies should be evaluated for diabetesto aid in counseling concerning cause andrecurrence risks. Am. J. Med. Genet. 90:303–309, 2000. © 2000 Wiley-Liss, Inc.
KEY WORDS: oculoauriculovertebral ;hemifacial microsomia; Gold-enhar “syndrome”; diabeticembryopathy; maternal dia-betes; teratogen
INTRODUCTION
Infants born to diabetic mothers have a three- to six-fold higher rate of malformation than infants born tonondiabetic mothers [Kucera, 1971; Pederson et al.,1964]. Caudal dysgenesis is classically linked to mater-nal diabetes [Williamson, 1970], but many other typesof anomalies including congenital heart defects, renalanomalies, and neural tube defects are described fre-quently [Gonzalez et al., 1989; Khoury et al., 1989; No-vak and Robinson, 1994; Robin et al., 1996; Tyral,1996]. However, craniofacial anomalies have been de-scribed in only a small number of reports [Becerra etal., 1990; Johnson et al., 1983; Ramos-Arroyo et al.,1992]. Patients have been described with the femoral-facial syndrome [Daentl et al., 1975; Hurst andJohnson, 1980; Johnson et al., 1983] and auricular ab-normalities including microtia and preauricular tagsas a consequence of maternal diabetes [Berkenstadt etal., 1991; Johnson and Fineman, 1982; Lin et al., 1998].
Hemifacial microsomia includes unilateral microtiawith ipsilateral macrostomia and mandibular hypopla-sia. A variant of this is the oculoauriculovertebral com-plex (Goldenhar “syndrome”), which comprises verte-bral abnormalities, epibulbar dermoids, and otheranomalies [Bassila and Goldberg, 1989]. Hemifacialmicrosomia and the Goldenhar phenotype probably arevariants of the same condition, but they differ in com-plexity and severity [Cousley and Wilson, 1992; Kayeet al., 1989]. The causes and pathogenesis of this entityare not well known but are likely heterogeneous. Thereare previous reports [Grix, 1982; Grix, et al., 1982; Linet al., 1998] of oculoauriculovertebral malformationsoccurring in infants of diabetic mothers.
*Correspondence to: Mahin Golabi, M.D., M.P.H., Dept. of Pe-diatrics, Division of Medical Genetics, University of CaliforniaSan Francisco, 533 Parnassus Ave, Box 0706, San Francisco, CA94143.
Received 16 July 1999; Accepted 17 October 1999
American Journal of Medical Genetics 90:303–309 (2000)
© 2000 Wiley-Liss, Inc.
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Over the years, we have observed infants born todiabetic mothers with craniofacial anomalies not wellrecognized as part of the diabetic embryopathy. There-fore, we studied the possible relationship between cra-niofacial anomalies and maternal diabetes. In thisreport we describe 21 individuals born to diabeticmothers who have anomalies including hemifacial mi-crosomia, microtia, hearing loss, facial nerve palsy,epibulbar dermoids, microopthalmia, and vertebralanomalies, including segmentation defects.
MATERIALS AND METHODS
We retrospectively ascertained two patient popula-tions born to insulin dependent or oral hypoglycemictreatment-dependent diabetic mothers, whose diabeteswas diagnosed prior to pregnancy; all patients hadshared features including hemifacial microsomia, mi-crotia, and hearing loss. We excluded individuals bornto mothers with isolated gestational diabetes, and weselected only those patients with good medical records,including complete prenatal histories. We also ex-cluded cases with a known chromosomal abnormality,autosomal dominant hemifacial microsomia, or a rec-ognizable syndrome including Townes-Brocks syn-drome, branchio-oto-renal syndrome, Treacher Collinssyndrome, or Nager syndrome. The first group wascomprised of individuals evaluated through geneticsservices for malformations; the second was comprisedof individuals identified through a database search inour craniofacial clinic. A clinical geneticist evaluatedpatients in both populations.
The first group consisted of 14 individuals selectedfrom patients seen in our genetics services who fit ourselection criteria. The second group consisted of sevenindividuals identified from a craniofacial databasesearch of patients who were seen between 1988 and1998 and who had hemifacial microsomia; 126 casesidentified were reviewed for complete prenatal historyincluding documentation of maternal diabetes status.Cases without a complete prenatal history were ex-cluded; they included patients with no prenatal his-tory, children who were adopted, and children in thefoster care system. There were also infants of mothersin whom glucose status was not known or the resultswere not available; 38 of the 126 cases had completeprenatal records. Of these 38, three individuals wereborn to mothers with gestational diabetes and were notincluded in this study to keep our criteria for inclusionmore stringent. Of the remaining 35, seven cases metall criteria for this retrospective study and are de-scribed in this report.
RESULTS
Group I consisted of six females and eight males(Table I). There is one set of sibs (a brother and sisterpair). Group II consisted of seven females (Table II). Allmothers in both groups had diabetes documented priorto pregnancy. A brief description of each individualis in Tables I and II with a summary of all cases inTable III. Craniofacial anomalies of two individualsrepresentative of the two groups are shown in Figures1 and 2.
TABLE II. Summary of Clinical Findings of Individuals in Group II*
Case Sex GA BW AuricularFacial
anomalies OcularVertebral/skeletal CNS/other
1 F 34 wks 1,500 Hearing loss Hemifacialmicrosomia
L. microopthalmia Absent corpuscallosum
L. macrostomia Intracranial lipomaL. cleft lip
and palate,L. skin tags
2 F ? 1,800 Preauricular tags L. hemifacialmicrosomia
C2 & C3 fusion
3 F Term 3,267 Preauricular tag Hemifacialmicrosomia
L. microtia Cleft palateFacial palsy
4 F Term ? B. microtia Branchial cystsHearing lossL. preauricular pits
Hemifacialmicrosomia
Facial palsy5 F Term ? C. hearing loss B. hemifacial
microsomiaEpibulbar
dermoidsCervical fusion
Sprengledeformity
6 F Term ? R. microtiaB. preauricular
tags
B. hemifacialmicrosomia
Macrostomia7 F 34 wks 2,200 B. preauricular
tagsM. hearing lossStenotic L. Canal
B. hemifacialmicrosomia
Hypoplastic tearducts
B. conjunctivaldermoids
TorticollisHypoplastic
thumbs
Small kidneysPDA
*GA: gestational age; L: left; B: bilateral; BW: body weight; ?: unavailable/unknown; R: right; C: conductive; M: mixed, PDA: patent ductus arteriosus.
Diabetic Embryopathy 305
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All patients shared a common pattern of anomaliesthat included hemifacial microsomia, facial nervepalsy, epibulbar dermoids, microtia, hearing loss, andvertebral anomalies. Hemifacial microsomia was seenin 50% of our patients from group I and 100% of ourpatients from group II; epibulbar dermoids in 21% ofour patients from group I and 29% of our patients from
group II; microtia in 57% of our patients from group Iand 43% of our patients from group II; vertebral orskeletal anomalies in 57% of our patients from group Iand 43% of our patients from group II; and facial nervepalsy in 36% of our patients from group I and 29% ofour patients from group II. Our first patient group hadadditional findings. There were congenital heart
TABLE III. Clinical Findings in Offspring of Diabetic Mothers*
Anomaly Group I % Group II % Total
Anomalies of the face 11/14 79 7/7 100 85%Hemifacial microsomia 7/14 50 7/7 100Macrostomia/lateral facial cleft 2/14 14 2/7 29Cleft lip/palate 1/14 7 2/7 29Micrognathia 2/14 14 0/7 0Branchial cleft cyst 0/14 0 1/7 14Short nose 2/14 14 0/7 0Fat pad across nose 2/14 14 0/7 0Facial skin tags 2/14 14 1/7 14
Ocular anomalies 7/14 50 3/7 43 48%Lens opacity 1/14 7 0/7 0Microophthalmia/optic nerve hypo. 2/14 14 1/7 14Epibulbar dermoid/ocular lipoma 3/14 21 2/7 29Frontal nasal dysplasa 1/14 7 0/7 0Laterally displaced inner canthi 1/14 7 0/7 0Tear duct obstruction 1/14 7 1/7 14
Auricular anomalies 13/14 93 7/7 100 95%Microtia 8/14 57 3/7 43Sensorineural/conductive hearing loss 5/14 36 4/7 57Preauricular pits 3/14 21 1/7 14Preauricular tags 4/14 29 4/7 57Anotia 1/14 7 0/7 0Atretic ear canal 2/14 14 1/7 14Additional ear malformations 5/14 36 1/7 14
CNS anomalies 7/14 50 3/7 43 48%Absent corpus callosum 0/14 0 1/7 14Intracranial lipoma 0/14 0 1/7 14Pineal lipoma 1/14 7 0/7 0Facial nerve palsy 5/14 36 2/7 29Calcification of falx cerebi 2/14 14 0/7 0
Congenital heart defect 4/14 29 0/7 0 19%VSD 3/14 21 0/7 0ASD 1/14 7 0/7 0Double outflow right ventricle 1/14 7 0/7 0Pulmonary atresia 1/14 7 0/7 0Coarctation of the aorta 1/14 7 0/7 0Tricuspid regurgitation 1/14 7 0/7 0Cleft mitral valve 1/14 7 0/7 0Subaortic stenosis 1/14 7 0/7 0Right aortic arch 1/14 7 0/7 0
Vertebral/skeletal anomalies 8/14 57 3/7 43 52%Fused cervical vertebrae 3/14 21 2/7 29Hemivertebrae 1/14 7 0/7 0Torticollis 0/14 0 1/7 14Tethered cord 2/14 14 0/7 0Bifid/fused ribs 1/14 7 0/7 0Hip dislocation 1/14 7 0/7 0Femoral hypoplasia 2/14 14 0/7 0Radial clubbing 1/14 7 0/7 0Clubfoot 2/14 14 0/7 0Right bifid thumb 1/14 7 0/7 0Hypoplastic/absent thumb 1/14 7 1/7 14Radial hypoplasia 1/14 7 0/7 0
Genito-urinary anomalies 3/14 21 1/7 14 19%Duplicated right kidney 1/14 7 0/7 0Dysplastic cystic kidney 1/14 7 0/7 0Ectopic right kidney (pelvic) 1/14 7 0/7 0Small kidneys 0/14 0 1/7 14Hypospadias 1/14 7 0/7 0
*CNS: central nervous system; VSD: ventricular septal defect; ASD: atrial septal defect.
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anomalies in 29% of our patients from group I and innone of the patients from our second group. There wererenal or urogenital anomalies such as dysplastic kid-neys and ectopic kidneys in 21% of our patients fromgroup I and in 14% of our patients from group II.
DISCUSSION
The prevalence of diabetes mellitus in pregnantwomen is estimated to be 2–3% [Becerra et al., 1990],
so the 18% incidence of diabetes in the mothers of oursecond group of patients (seven of 38 patients with re-cords) is higher than one would expect by chance. Thissuggests a causal relationship between hemifacial mi-crosomia and maternal diabetes.
The clinical difference between the two groups islikely due to ascertainment bias because individualsseen by genetics were mostly infants in the neonatalintensive care unit who had multiple malformations,whereas individuals identified through the craniofacial
Fig. 2. Craniofacial findings of case 7 from Group II. Note hemifacial microsomia, and lateral displacement of inner canthi (A). Case 7 also hadabnormal formation of the concha, stenotic left canal (B) and bilateral preauricular tags (C).
Fig. 1. Craniofacial findings of case 3 from Group I. Note right epibulbar dermoid, lateral displacement of inner canthi, and lateral clefting of the nosewith skin tags (A). Left hemifacial microsomia is mild except when smiling or crying. Note left microtia and preauricular tags (B).
Diabetic Embryopathy 307
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database were older and were frequently referred forcraniofacial anomalies.
When the frequency of anomalies seen in the twogroups is combined (Table III), a pattern of anomaliesemerges. Overall, 67% of individuals had hemi-facial microsomia; 52% had microtia; 43% had hearingloss including sensorineural, conductive, and mixedhearing loss; 24% had epibulbar dermoids; and24% had fused cervical vertebrae. These manifesta-tions all represent the oculoauriculovertebral (OAV)complex.
After observing that the clinical findings in bothgroups also pertain to the OAV/Goldenhar complex, wewere interested to know whether a causal relationshipbetween diabetes and the Goldenhar anomalies hadbeen shown previously. Cleft lip, cleft palate, and earabnormalities have been noted in infants of diabeticmothers [Becerra et al., 1990; Ramos-Arroyo et al.,1992]. Johnson and Fineman [1982] reported on twopatients, offspring of diabetic mothers, with branchialarch malformations including bilateral preauriculartags, microtia, micrognathia, hemifacial microsomia,tetralogy of Fallot, truncus arteriosus, and hemiverte-brae. The authors commented that the ocular, auricu-lar, vertebral, and cardiac anomalies suggest the diag-nosis of Goldenhar anomaly, but the lack of otherfindings, including epibulbar dermoids, was thought torule this out. Our data support this relationship be-tween diabetes and the OAV/Goldenhar complex. Fourof our patients had epibulbar dermoids and had addi-tional anomalies of the Goldenhar phenotype. Addi-tional reports also support these associations. Berken-stadt et al. [1991] described an infant of a diabeticmother with bilateral microtia and cardiovascularanomalies, and Ziereisen et al. [1997] reported on aninfant born to a mother with insulin-dependent diabe-tes with micrognathia, femoral hypoplasia (a charac-teristic finding of infants of diabetic mothers), and con-genital heart anomalies. They thought that this infantwas similar to that reported by Berkenstadt et al.[1991] and that they both could have a diabetic fetopa-thy.
One patient presented here had additional findingsincluding midline defects and facial-femoral anomalies.Case 3 in Group I has a pineal lipoma; lateral place-ment of inner canthi; lateral clefting of nose with skintags (Fig. 1); asymmetric face; epibulbar dermoid; mi-crotia; preauricular tags; facial clefting; high archedpalate; and femoral hypoplasia. The femoral-facial syn-drome was first described in the mid-1970s to 1980swith diabetes in some of the mothers and is character-ized by short nose, hypoplastic alae nasi, and hypoplas-tic femurs [Daentl et al., 1975; Hurst and Johnson,1980; Johnson et al., 1983].
An increase in craniofacial malformations in the off-spring of diabetic rats, particularly mandibular andmaxillary hypoplasia, has been documented [Padma-nabhan and Al-Zuhain, 1987]. Fetuses of diabetic ratswith micrognathia have also been found to have a dis-turbance in the production of mandibular chondroitinsulfate proteoglycans [Unger and Eriksson, 1992]. In areview of diabetic embryopathy in experimental ani-mals, Freinkel [1988] observed that, as with other tera-
togens, there may be interplay between environmentalagents and the genetic predisposition to certain anoma-lies. Anomalies are not seen in the offspring of everydiabetic. Also, glucose may not be the only teratogenicagent to which the fetus of a diabetic mother is ex-posed. A number of other abnormalities including in-creased osmolarity and abnormal levels of ketones,amino acids, and fatty acids may all contribute topathogenesis.
In conclusion, the list of teratogenic effects of mater-nal diabetes should include hemifacial microsomia andother anomalies associated with the OAV complex. In-fants of diabetic mothers should be evaluated for cra-niofacial anomalies including hearing loss and indi-viduals with OAV/Goldenhar complex assessed formaternal diabetes exposure.
REFERENCES
Bassila MK, Goldberg R. 1989. The association of facial palsy and/or sen-sorineural hearing loss in patients with hemifacial microsomia. CleftPalate J 26:287–291.
Becerra JE, Khoury MJ, Cordero JF, Erickson JD. 1990. Diabetes mellitusduring pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 85:1–9.
Berkenstadt M, Shtrausberg R, Goodman RM, Katznelson MB-M, Gold-man B, Barkai G. 1991. Concordance of auriculo-cardiovascular-skeletal malformations: a new malformation complex in an infant of adiabetic mother? Am J Med Genet 41:26–29.
Cousley RRJ, Wilson DJ. 1992. Hemifacial microsomia: developmental con-sequence of perturbation of the auriculofacial cartilage model? Am JMed Genet 42:461–466.
Daentl DL, Smith DW, Scott CI, Hall BD, Gooding CA. 1975. Femoralhypoplasia-unusual facies syndrome. J Pediatr 86:107–111.
Freinkel N. 1988. Diabetic embryopathy and fuel-mediated organ terato-genesis: lessons from animal models. Horm Metabol Res 20:463–475.
Gonzalez A, Krassikoff N, Gilbert-Barness EF. 1989. Polyasplenia complexwith mesocardia and renal agenesis in an infant of a diabetic mother.Am J Med Genet 32:457–460.
Grix A, Curry C, Hall BD. 1982. Patterns of multiple malformations ininfants of diabetic mothers. BD: OAS 18:55–77.
Grix A. 1982. Invited editorial comment: Malformations in infants of dia-betic mothers. Am J Med Genet 13:131–137.
Hurst D, Johnson DF. 1980. Brief clinical report: femoral hypoplasia-unusual facies syndrome. Am J Med Genet 5:255–258.
Johnson JP, Carey JC, Gooch WM, Petersen J, Beattie JF. 1983. Femoralhypoplasia-unusual facies syndrome in infants of diabetic mothers. JPediatr 102:866–872.
Johnson JP, Fineman RM. 1982. Branchial arch malformations in infantsof diabetic mother: two case reports and a review. Am J Med Genet13:125–130.
Kaye CI, Rollnick BR, Hauck WW, Martin AO, Richtsmeier JT, NagatoshiK. 1989. Microtia and associated anomalies: statistical analysis. Am JMed Genet 34:574–578.
Khoury MJ, Becerra JE, Cordero JF, Erickson JD. 1989. Clinical-epidemiologic assessment of patterns of birth defects associated withhuman teratogens: application to diabetic embryopathy. Pediatrics 84:658–665.
Kucera J. 1971. Rate and type of congenital anomalies among offspring ofdiabetic women. J Reprod Med 7:61–70.
Lin HJ, Owens TR, Sinow RM, Fu PC, DeVito A, Beall MH, Lachman RS.1998. Anomalous inferior and superior venae cavae with oculoauricu-lovertebral defect: review of Goldenhar complex and malformations ofleft-right asymmetry. Am J Med Genet 75:88–94.
Novak RW, Robinson HB. 1994. Coincident DiGeorge anomaly and renalagenesis and its relation to maternal diabetes. Am J Med Genet 50:311–312.
Padmanabhan R, Al-Zuhair AGH. 1987. Congenital malformations and
308 Ewart-Toland et al.
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intrauterine growth retardation in stretozotocin induced diabetes dur-ing gestation in the rat. Reprod Toxicol 1:117–125.
Pederson LM, Tygstrup I, Pederson J. 1964. Congenital malformations innewborn infants of diabetic women. Correlation with maternal diabeticvascular complications. Lancet 1:1124–1126.
Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. 1992. Maternaldiabetes: the risk for specific birth defects. Euro J Epidemiol 8:503–508.
Robin NH, Ko LM, Heeger S, Muise KL, Judge N, Bangert BA. 1996.Syntelencephaly in an infant of a diabetic mother. Am J Med Genet66:433–437.
Tyral EE. 1996. The infant of the diabetic mother. Diabetes Preg 23:220–241.
Unger E, Eriksson UJ. 1992. Regionally disturbed production of cartilageproteoglycans in malformed fetuses from diabetic rats. Diabetologia35:517–521.
Williamson DAJ. 1970. A syndrome of congenital malformations possiblydue to maternal diabetes. Develop Med Child Neurol 12:145–152.
Ziereisen F, Courtens N, Clercx A, Perlmutter N. 1997. Maternal diabetesand fetal malformations: a case associating cardiovascular, facial, andskeletal malformations. Pediatr Radiol 27:945–947.
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