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Keywords:

  • chromosomal aberrations;
  • cleft lip;
  • fetus;
  • prenatal diagnosis;
  • trisomy 18;
  • ultrasound

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES

Objective

To investigate the clinical implications of two categories of fetal bilateral cleft lip and palate (BCLP): with premaxillary protrusion and with a flattened profile.

Methods

This was a retrospective study of fetuses with a prenatal diagnosis of BCLP at the Department of Obstetrics and Gynecology of the University of Bologna in the period 1991–2005.

Results

BCLP was diagnosed prenatally in 14 cases (mean gestational age at diagnosis, 21 (range, 12–36) weeks). In nine of these, there was a premaxillary pseudomass; in the remaining five, the profile was flat. Associated structural and/or chromosomal anomalies were found in two of the nine with a premaxillary pseudomass and in all five of those with a flat profile (P = 0.02). All fetuses with a flat profile had aneuploidies (three trisomy 18, one trisomy 13, one trisomy 8 mosaic), as did one of the nine with a premaxillary pseudomass. Eight of the pregnancies were terminated, including three of those with a premaxillary pseudomass and all five of those without. All continuing pregnancies resulted in live births, although one neonate affected by Krabbe's disease died shortly after birth.

Conclusions

Our findings suggest that a third of cases of BCLP diagnosed in utero have a flat profile and these are at high risk of lethal aneuploidies. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES

Bilateral cleft lip and palate (BCLP) is a correctable malformation that may, however, be associated with other severe anomalies including aneuploidies. BCLP is frequently found with premaxillary protrusion, which results in a typical ultrasound image1–3. In some cases, however, there is no protrusion, and the profile appears flat3. The aim of our study was to investigate the relative frequency and prognostic implications of these two types of BCLP.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES

During a 14-year period (1991–2005), 14 fetuses with BCLP were identified by ultrasound in the Department of Obstetrics and Gynecology of the University of Bologna. In all cases, a multiplanar evaluation of the fetal face was obtained using transverse, sagittal and coronal planes, as described previously4. In those cases occurring after 1999, three-dimensional ultrasound was also employed5, 6. The fetuses were divided into two groups according to the presence of a premaxillary protrusion (Figure 1) or a flat profile (Figure 2). Karyotyping was performed in all 14 cases: two chorionic villi biopsies, eight amniocenteses and four cordocenteses. Postnatal follow-up was carried out mainly by telephone interview and postmortem examination. In only one case was there no follow-up.

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Figure 1. Bilateral cleft lip and palate with premaxillary protrusion (arrow): three-dimensional sonograms (a–c) at 30 weeks' gestation compared with postnatal appearance (d).

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thumbnail image

Figure 2. Bilateral cleft lip and palate without premaxillary protrusion: (a) profile of the fetus at 12 weeks' gestation demonstrating the flat face and increased nuchal translucency thickness; (b) axial view of the alveolus demonstrating bilateral clefts (arrows); (c) three-dimensional sonogram at 15 weeks' gestation confirming the flat face and bilateral cleft; (d) postmortem appearance of the fetus (terminated at 15 weeks), which was affected by mosaic trisomy 8.

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Fisher's exact test was used to compare the difference between the incidence of anomalies in the two groups.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES

Fourteen cases of BCLP were diagnosed antenatally during the study period, at a mean gestational age of 21 (range, 12–36) weeks. In nine of these, the diagnosis was made at < 23 weeks (the age up to which termination of pregnancy is permitted by law) and in two cases it was at 12 weeks. In all cases, the clefts were clearly identified with ultrasound in axial and coronal planes using either standard two-dimensional ultrasound or a combination of two-dimensional and three-dimensional ultrasound, as described previously4, 6.

In nine cases, a premaxillary protrusion was detected, and two of these fetuses had associated anomalies (Table 1). Three of these fetuses underwent termination of pregnancy (TOP). Of the remaining six that were live born, one died in the perinatal period and five survived.

Table 1. Associated anomalies in fetuses with bilateral cleft lip and palate (BCLP) and gestational age (GA) at diagnosis
BCLP with:GA at diagnosis (weeks)Associated anomalies
StructuralChromosomal
  • *

    Number with associated anomalies/number with the diagnosis.

Premaxillary pseudomass (n = 2/9)*22Microphthalmia and esophageal atresia 
 24PolydactylyTrisomy 13
Flat profile (n = 5/5)*12Megacisterna magna, cerebellar hypoplasia, univentricular heart and polydactylyTrisomy 13
 20Choroid plexus cysts and ventricular septal defectTrisomy 18
 15Strawberry-shaped headTrisomy 18
 15PolydactylyTrisomy 18
 12Mosaicism trisomy 8

In five cases there was no protrusion of the premaxilla. In these cases the profile was always flat, with a very flattened nose. All these fetuses had chromosomal aberrations and in four there were other anatomical deformities (Table 1). All of these fetuses underwent TOP. There was a statistically significant difference in the rate of associated anomalies between the two groups (Fisher's exact test, P = 0.02).

In the six continuing pregnancies, all with premaxillary protrusion, serial ultrasound examinations were performed throughout gestation, and the fetal profile did not undergo further modification; the protrusion of the premaxilla had a similar appearance in early as well as in late gestation.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES

Cleft lip and palate is one of the most frequent congenital anomalies, with an incidence of approximately 1 in 500–1 in 1000 live births7. BCLP is the type of facial cleft that is known to be most frequently associated with other anomalies3, 8. Our results confirm that the prevalence of extrafacial malformations and aneuploidies is indeed very high in these cases. Our results also suggest that two rather different categories of BCLP exist: one with premaxillary protrusion and one with a flattened profile. In terms of associated anomalies, the difference between these two types is striking. Albeit our series was relatively small, it is noteworthy that all fetuses with a flat profile had lethal chromosomal aberrations.

We did not perform a detailed autoptic study of the affected fetuses and infants, but a review of the postnatal and post-termination images suggests that the pathogenesis of the craniofacial malformation is likely to be different in these two groups. Fetuses with BCLP and a flat profile present underdevelopment of the central portion of the face which resembles very closely that encountered with severe forms of holoprosencephaly. We suggest that in these cases the malformative process is more complex and extreme than that encountered when there is a premaxillary protrusion, which may help in explaining the different rate of associated anomalies.

Nyberg et al.3 first reported that BCLP can be associated with either premaxillary protrusion (Type IIIa according to their original classification) or with a flat profile (Type IIIb). It would seem from our experience that the latter type has a rather strong similarity with midline cleft lip (Type IV). Both malformations have in common a very high prevalence of associated aneuploidies and hypoplasia of the midface.

We also confirmed that early prenatal diagnosis of BCLP is possible9. In two of our cases the condition could be recognized at 12 weeks, during scans performed to measure nuchal translucency thickness. In both cases, suspicion of BCLP arose due to an abnormality of the fetal profile, in one case because of a premaxillary pseudomass and in the other because of an unusual flatness of the face. Although our experience is limited, it does not seem that in BCLP the fetal profile undergoes modification throughout gestation. The presence or absence of the protrusion could be seen as early as the late first trimester and was not found to change subsequently.

In conclusion, our findings suggest that one third of cases of BCLP identified in utero are associated with a flat profile. These fetuses have a very high risk of lethal aneuplodies and trisomy 18 in particular. Both a premaxillary pseudomass and a flat profile should alert the sonologist to the the possible presence of facial clefts as early as the late first trimester.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. REFERENCES