Introduction

The Stickler syndrome or hereditary progressive arthroophthalmopathy is a rare connective tissue disorder estimated to affect approximately 1/7,500 newborns [1]. The syndrome was first described by Stickler in 1965 [2] and phenotype includes degeneration of the vitreous gel and retina, myopia, craniofacial dysmorphisms, hearing impairment, skeletal dysplasia and progressive arthropathy. Mutations at three collagen loci COL2A1, COL11A1 and COL11A2 were found in Stickler syndrome patients [3, 4], with about two-thirds of investigated familial cases found to be associated to COL2A1 gene mutations [5]. An association between Stickler syndrome and Pierre-Robin sequence was reported [6, 7].

Cleft or bifid uvula, a small division or split in the midline of the uvula, is considered as a partial cleft palate (CP) of the smallest degree [8]. The prevalence of some form of uvular cleft was observed in 2.26 % of 709 children with the highest prevalence among Caucasian, in agreement with a previous incidence of 1.44 % on 9,701 adult Caucasians as reported by Meskin et al. [9].

Visualization of the soft palate was particularly problematic because of its curved anatomical arrangement, shadowing by neighboring tissues and difficulty in its discrete recognition on ultrasound examination due to lack of a landmark [10]. In a series by Cash et al. [11], 67 % of the cases were isolated cleft lip, 93 % were cleft lip and palate (CLP) while only 22 % were isolated CP.

The fact that the prenatal detection rate of CP is very low (0–1.4 %) demonstrates that the difficulty of visualizing CP during routine examination [11–16] and that there are no satisfactory indicators of an isolated CP [10]. The palate cannot be visualized in its entirety in a single conventional plane by 2D ultrasound as the soft palate lays at 30° to the primary. The secondary palate gradually increases in its curvature (in both sagittal and coronal planes) as the uvula lengthens with advancement of gestation. The uvula is a good landmark for directing the examination plane to the soft palate. The optimal time for visualization of the soft palate is beyond 20 weeks’ gestation, possibly at around 23–24 weeks, when the uvula could be identified consistently as a definitive structure and the palatal arch is present but not very marked. Nevertheless, as the soft palate can be seen also before 20 weeks’ gestation, especially in the sagittal plane, a sonographic search of this anatomical structure should be sought at the time of routine second trimester scan. 3D ultrasound has provided evidences to represents a new technical approach to the study of fetal palate and different techniques were developed [17–20]. However, actually 3D ultrasound is not systematically used during routine second trimester scan as it requires specific operators training and quality imaging is dependent upon acquisition of excellent volume data sets for offline analysis.

In a work by Wilhelm and Borgers [10], visualization of either the uvula or the soft palate was successful in 98.4 % of the cases using 2D ultrasound. A case of an isolated CP in a normal fetus was diagnosed while in one case with CLP, the CP and the completely split uvula were detected. Wilhelm and Borgers [10] concluded that absence of the “equals sign” indicates CP and should prompt further examination of the soft palate in a median sagittal section.

Case report

A 37-year-old woman, G5P4, was referred to our tertiary Prenatal Diagnostic Center at 30 weeks of gestation for detailed scan following an unremarkable second trimester scan performed elsewhere. The woman had a positive familial history of Stickler syndrome, as shown in the genealogical tree (Fig. 1).

Fig. 1
figure 1

Genealogic tree of the Family affected by Stickler syndrome

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The ultrasound examination was carried out in 2004 using a Technos MPX (Esaote, Genoa, Italy) equipped with a 3.5–5 MHz transabdominal probe. With the fetus lying in supine position, a normal hard and soft palate could be seen by means of 2D- and Doppler sonography. A scanning section of the fetal head in oblique plane allowed the operator to detect a previously undiagnosed median cleft at the level of the uvula (Fig. 2).

Fig. 2
figure 2

Transabdominal scan performed at 30 week’s gestation with the fetal head in oblique plane showing a previously undiagnosed median cleft at the level of the uvula (red arrows)

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Amniocentesis was performed after genetic counseling and signed informed consent for fetal karyotyping and molecular biology analysis. Linkage polymorphism of the 3-prime-VNTR (variable-number tandem repeat) COL2A1 gene located on chromosome 12q13.11 was performed and showed normal 46, XY with mutation of the allele 3. No other congenital malformations could be demonstrated. Genetic and multispecialist counseling to the couple was undertaken and pediatric and neonatologist team were available at the time of delivery.

A baby weighing 3,760 g with normal 1- (9) and 5-min (10) Apgar score was born at term by normal vaginal delivery. The boy underwent serial follow up examination by a pediatric surgical team, with confirming of the prenatally 2D ultrasound diagnosis (Fig. 3).

Fig. 3
figure 3

Anatomical details of the bifid uvula (U), adenoid tissue (AT) and palatine crura (PC) before surgical correction

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Surgical correction of the bifid uvula was performed at 4 year postnatal life. The updated outcome comprises a mild to moderate deafness partially corrected by acoustic implants, a right blindness by the age of 6 following a severe retinal detachment and left eye cerclage due to vitreoretinopathy.

Discussion

Different geno- and phenotypes of Stickler syndrome were recognized and reported in Table 1. This connettive tissue disorder has a variable expression.

Table 1 Phenotype, Mendelian inheritance in man (MIM), gene locus, chromosome location and mode of inheritance of Stickler syndrome
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In our studied Family, the patient number 2 (female) of the third generation shows postnatally the following congenital anomalies: cleft of the soft palate, myopia, right retinal detachment, muscle-skeletal disorders, mild deafness, dental anomalies, and mitral valve prolapsed. The patient number 3 (female) of the third generation shows postnatal a cleft of the soft palate, myopia of high degree, hypotonia, psychomotor impairment, and complicated dental anomalies. The patient number 5 of the third generation (male) was studied prenatally with Level II sonographic examination that was initially performed elsewhere. The certificate referred to “a presumptive normal hard and soft palate” by means of 2D and Doppler ultrasound. When the patient was scanned at 30 weeks of gestation at our prenatal diagnostic tertiary care center, the favourable supine fetal position and the swallowing movements enabled the operator to detect, in an oblique coronal plane, a previous unrecognized bifid uvula.

In recent years, 3D ultrasound has provided evidences to represents a new technical approach to the study of fetal palate and different techniques were developed [17–20]. Nevertheless, 3D ultrasound is not systematically used during routine second trimester scan as it requires specific operators training and quality imaging is dependent upon acquisition of excellent volume data sets for offline analysis.

Nonetheless, when skill operators and ultrasound machine equipped with commercially software are available, 3D–4D ultrasound may aid the prenatal visualization and thus detection of CP, especially those involving the soft palate and the uvula. Of course, yawning and swallowing movements resulting in a fluid-filled pharynx physiologically improve the visualization of these structures [21].

Although this useful “visualization window” cannot be captured with only one volume, 3Dlive/4D may be applied.

Chosack and Eidelman [22] defined a cleft uvula as a distinct bifurcation of at least one-fourth of the total uvula length and reported prevalence of only 0.44 % among a population of 70.359 children ages 6–18 residing in Israel.

In a series of 667 singleton pregnant women referred for detailed anomaly scan between 20 and 25 weeks of gestation, Wilhelm and Borgers [10] were able to visualize the uvula during routine 2D ultrasound examination as an “equals sign” in 90.7 % and the soft palate in 85.3 %, respectively, in a median sagittal section. Visualization of either the uvula or the soft palate was successful in 98.4 % of the cases. A case of an isolated CP in a normal fetus was diagnosed while in one case with CLP, the CP and the completely split uvula were detected. These authors [10] concluded that absence of the “equals sign” indicates CP and should prompt further examination of the soft palate in a median sagittal section.

In our “historical” case diagnosed before the “equals sign” was proposed as a useful ultrasound landmark of the fetal uvula, the 2D ultrasound diagnostic cluster was a cleft involving medially and almost completely the uvula. The good snapshot of the bifid uvula was captured in an oblique plane and was aided by fetal swallowing movements.

Moreover, the ultrasound diagnosis of bifid uvula elicited a late amniocentesis with molecular biology analysis that could demonstrate a 3-prime-VNTR COL2A1 mutation on chromosome 12q13.11 enabling a prenatal diagnosis of Stickler syndrome.

The genetic investigation further revealed that the sibling had inherited the allele 3 from the mother that in this Family is responsible for the Stickler syndrome. The molecular biology investigation could also excluded overlapping autosomal dominant disorders involving mutation in the COL2A1 gene and including achondrogenesis type II, spondyloepimetaphyseal dysplasia Strudwick type, spondyloperipheral dysplasia, platyspondylic lethal skeletal dysplasia Torrence type, osteoarthritis with mild chondrodysplasia and rhegmatogeneous retinal detachment; autosomal disorders involving mutation in the COL11A1 such as Marshall syndrome or those involving COL11A2 mutation such as otospondylometaphyseal dysplasia, Weissenbach–Zwymuller syndrome and nonsyndromic sensorineural hearing loss (Table 2).

Table 2 Overlapping disorders involving mutation on COL2A1, COL11A1, COL11A2 with MIM number, gene locus and clinical phenotype
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Furthermore, the prenatal diagnosis allowed appropriate genetic and multispecialist counseling with estimation of recurrence risk and made pediatric and neonatologist team assistance at the time of birth available. This is extremely importance in case of autosomal dominant type of Stickler syndrome as in our reported case because affected individuals have a 50 % chance of passing on the mutation to each offspring.

Beside maxillo-facial surgery, that in our case occurred at the age of four, affected individuals should undergo annual examination by a vitreoretinal specialist, audiologic evaluations every 6 months through age of 5 years, then annually thereafter, screening for mitral valve prolapse on routine examination.