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A New Phenotypical Variant of Intrauterine Growth Restriction?

^a Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese
^b Laboratory of Ultrasonology, Department of Neurosciences
^c Clinical Audiology Unit, Dipartimento Cefalico-scheletrico, Azienda Ospedaliera Universitaria Senese, AOUS Nose and Throat
ⁱ Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Siena, Italy
^h Neonatal Audiologic Screening Service, USL7, Siena, Italy
^f Division of Neonatology, Perrino Hospital, Brindisi, Italy
^j Clinical Physiology Institute, National Research Council of Italy (IFC-CNR), Lecce Section, Italy
^e Medical Genetics Unit, Ospedale Di Venere, Bari, Italy
^g Division of Obstetrics and Gynecology, Guastalla Civil Hospital, AUSL Reggio Emilia, Guastalla, Italy
^d Service d'Anatomie et de Cytologie Pathologiques, Hôpital Necker-Enfants-Malades, Paris, France

	ABSTRACT

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OBJECTIVES. A link between intrauterine growth restriction and major adult-onset diseases has been reported. In this study we observed a series of hitherto-unrecognized clinical features in a population of children with intrauterine growth restriction.

PATIENTS AND METHODS. A total of 77 Italian children (aged 9.45 ± 2.08 years) with antenatally diagnosed intrauterine growth restriction and small-for-gestational-age birth, along with their parents, were examined. The children with intrauterine growth restriction and were small for gestational age were subdivided into 2 groups ("variant" versus control subjects) according to evidence of auricle morphology deviation from normal. The following variables were determined: (1) external ear auricle geometry; (2) function of the posterior communicating arteries of the circle of Willis, as assessed by transcranial Doppler ultrasonography; (3) articular mobility, as assessed by Beighton's 9-point scale; (4) skin softness; and (5) distortion product–evoked otoacoustic emissions.

RESULTS. Intrauterine growth restriction–variant children (n = 27) showed a significant female predominance, a lower proportion of maternal pregnancy-induced hypertension/ preeclampsia, and a higher head circumference as compared with intrauterine growth restriction control subjects. Mothers of small-for-gestational-age–variant children showed significantly different auricular geometry parameters as compared with the intrauterine growth restriction controls mothers. An excess of bilaterally nonfunctioning posterior communicating arteries was observed both in the children with the intrauterine growth restriction–variant phenotype and their mothers as compared with the control groups. Significantly increased proportions of joint hypermobility and skin softness were observed in the intrauterine growth restriction–variant children as compared with controls subjects. Children with the intrauterine growth restriction–variant phenotype and their mothers showed bilateral distortion product–evoked otoacoustic emissions notches versus none in the control subjects, with an associated reduction of the area under the curve in both the intrauterine growth restriction–variant children and their mothers. No significant differences between the variant and control groups regarding the fathers were observed.

CONCLUSIONS. We propose that the observed phenotypical constellation may represent an unrecognized variant of intrauterine growth restriction.

Key Words: intrauterine growth restriction • circle of Willis • auricle • joint hypermobility • skin • marker

Abbreviations: IUGR—intrauterine growth restriction • SGA—small for gestational age • PCoA—posterior communicating artery • LA—longest axis of the auricle • SA—shortest axis of the auricle • SA-D—distance of SA from the lowest auricle point • CCA—common carotid artery • DPOAE—distortion product–evoked otoacoustic emission • AUC—area under the curve • SPL—sound pressure level • ECM—extracellular matrix

Intrauterine growth restriction (IUGR) has a prevalence of 10% among all pregnancies, varying from rates of 3% to 5% among healthy mothers up to 25% in high-risk groups.¹ IUGR resulting in birth weight small for gestational age (SGA) is a known risk factor for high perinatal morbidity and mortality and has been related previously to development of several of the major diseases of later life, including coronary heart disease, obesity, noninsulin dependent diabetes, hypertension, and stroke.^2,3 Studies linking IUGR with long-term adverse health consequences have so far depended on crude measures of fetal growth, such as overall weight or length. Recently, fetal growth of liver and kidneys has been shown to be impaired in intrauterine growth-retarded infants, thus supporting the concept that fetal environmentally caused "programming" may increase the risk of functional defects and diseases in later life.⁴ However, no morphologic markers of impaired fetal growth that persist later in life are known to date, with the possible exceptions of fingerprints pattern abnormalities and shape of the palm⁵ or a high second-to-fourth-digit finger-length ratio^6,7 in specific SGA subsets. Here, we describe a series of children with idiopathic IUGR/SGA showing previously unrecognized, phenotypical features, including auricle shape variations, bilaterally reduced or absent hemodynamic responses of the posterior communicating arteries (PCoAs) of the circle of Willis, joint hypermobility, soft skin, and bilateral subclinical cochlear dysfunction.

	METHODS

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Subjects
A total of 77 Italian children (boys: 32; girls: 45; gestational age at birth: 35.49 ± 2.50 weeks; age at examination: 9.45 ± 2.08 years) with antenatally diagnosed IUGR (as defined as insufficient fetal growth <2 SD [or <3rd percentile] below the mean for gestational age) and SGA birth (as defined as insufficient body size <2 SD [or <3rd percentile] below the mean for weight and/or length in relation to gestational age and gender for the Italian population),^4,8 followed up in a regular clinical program, were enrolled, along with their parents (mothers, age at examination: 40.57 ± 4.61 years, range: 35–48 years; fathers, age at examination: 42.5 ± 0.71 years, range: 37–49 years). The examined families originated from Tuscany (67 of 77 [87%]), Apulia (8 of 77 [10.4%]), and Basilicata and Sicily (1 of 77 [1.3%] each). The percentiles for body height and weight at examination were determined on the basis of Italian cross-sectional growth charts.⁹ None of the participants had primary growth failure syndromes, congenital infections, known chromosomal aberrations, genetic syndromes, or showed specific dysmorphic features or developmental delay. None of the participants had a history of cerebrovascular disorders or preexisting systemic illness, known cochlear disease, history of environmental noise exposure, or inherited connective tissue diseases. After providing their respective histories, all of the subjects underwent a complete physical examination. Low maternal weight was defined as prepregnancy or delivery weight <45.36 kg or BMI 19.8 kg/m², and low maternal weight gain was defined as <0.27 kg per week.¹⁰ None of the mothers had a history of malnutrition and/or chronic use of alcohol or narcotics. None of the examined parents had a history of past or current smoking, hypertension, hypercholesterolemia, or diabetes mellitus. The IUGR/SGA children were subdivided into 2 groups (variant versus control subjects) according to subjective evidence of auricle morphology deviation from normal (Fig 1A), and the following variables were determined: (1) external ear auricle geometry; (2) PCoA function, as assessed by transcranial Doppler ultrasonography; (3) articular mobility; (4) skin softness; and (5) distortion product–evoked otoacoustic emissions (DPOAEs). The main reason for doing a long-term clinical follow-up in our IUGR/SGA children was an arterial pressure monitoring study.^11,12

View larger version (57K): [in this window] [in a new window]   FIGURE 1 Auricle shape in the IUGR/SGA variant and their mothers. A, Variant; B, IUGR/SGA control child; C, schematic graph; D and E, ear shape: right-to-left asymmetry in the mother of a child with the IUGR/SGA variant.

External Ear Geometry
The maximum width of longest axis (LA), shortest axis (SA) of the auricle, and the distance of SA from the lowest auricle point (SA-D) were measured (Fig 1A). SA/LA and LA/SA-D ratios were used as size-independent geometric indicators of auricle shape. The SA-D and SA/LA ratios from both ears were evaluated, and the mean of the measurements was used for each individual in the analyses. Morphometric measurements of the auricle were collected with Vernier calipers to 0.01-mm accuracy by 2 operators who were unaware of the results of the other clinical and/or instrumental findings. The asymmetry index was also calculated by subtracting the average length of the right side of the trait from the left and correcting for trait size (ie, 100 x right – left/[right + left]/2).¹³

Transcranial Color-Coded Duplex Ultrasonography
Ultrasound flow-flow examination was performed with a color-duplex scanner (Philips Sonos 5500, Agilent Technologies, Hewlett-Packard, Andover, MA), using either a 3- to 11-MHz linear transducer or a 2.5-MHz 90° sector transducer head for evaluating the extracranial carotid and vertebral arteries and the intracranial basal arteries, respectively. Examination of the internal carotid (intracranial tract), vertebral artery (V4 segment), and basilar artery, as well as in the anterior (precommunicating, A1 segment), middle (main trunk, M1 segment), and posterior (precommunicating and postcommunicating, P1-P2 segments) cerebral arteries through the temporal bone window, was performed according to standard techniques^14–16 (see Fig 2 for a diagram with the segments of the circle of Willis). All of the subjects showed sufficient acoustic windows. The blood flow velocity changes in the precommunicating parts (A1 and P1, respectively) of the anterior and posterior cerebral arteries were measured during common carotid artery (CCA) compression. To avoid a systemic cardiovascular reaction, compressions were applied for 3 to 5 cardiac cycles, low in the neck just proximal to the sternal head of the clavicle. The anterior communicating artery was defined as functional if blood flow was reversed in the ipsilateral A1 and enhanced in the contralateral A1 during CCA compression. The PCoA was considered to be functional if the flow velocity in the P1 was enhanced >20% during ipsilateral CCA compression. PCA was defined as fetal configuration (ie, the major stem of the PCA arising from the ipsilateral internal carotid artery instead of from the basilar artery) in case of significant decrease in peak velocity after CCA ipsilateral compression. The transcranial color-coded duplex ultrasonography was conducted by a single operator blind to further clinical or instrumental information. The methodology used was standard and sufficiently reproducible ( = 0.93 [SE: 0.021]; range: 0.89–1.0).

View larger version (50K): [in this window] [in a new window]   FIGURE 2 Schematic diagram of the arterial segments of the circle of Willis as identified by transcranial color-coded duplex ultrasonography.

Skin Softness
An excessive skin softness was evaluated as a subjective variable by 2 independent observers (interobserver agreement for increased skin softness: = 0.910 [SE: 0.025]; range: 0.846–1.0) who were unaware of the subjects' clinical history and findings.

Distortion Product–Evoked Otoacoustic Emissions
Otoacoustic emissions, expressing the response that the cochlea emits in the form of acoustic energy, are determined by the contractile activity of the outer hair cells and the mechanical and structural features of the basilar membrane. Otoacoustic emissions are currently used as objective indicators of cochlear pathology and used in several neonatal hearing loss screening programs.^20,21 In the present study, cochlear function (DPOAEs) was investigated in all of the IUGR/SGA children and their parents using an ILO 292 DP Echoport OAE Analyzer 5.0 (Otodynamics Ltd, London, United Kingdom).^22–24

Two simultaneous pure tones were sent to each ear (f2>f1 with an f2/f1 ratio = 1.22, sounds intensity = 70 dB sound pressure level, with a frequency range of 1–6 kHz). The degree of cochlear dysfunction was determined by calculating the area under the curve (AUC) for all of the DPOAE recordings. In case of a detectable "notch" (ie, a marked reduction in the intensity of otoacoustic emissions in the frequency response; Fig 3), its mean peak frequency was determined. All of the subjects had normal otoscopic findings and normal hearing, as preliminarily assessed using pure tone audiometry, tympanometry, stapedius reflex tests, and auditory brainstem responses.

View larger version (32K): [in this window] [in a new window]   FIGURE 3 DPOAEs in a child with the IUGR/SGA variant (A) and the corresponding mother (B). A notch (ie, a marked reduction in the frequency response) is evidenced (arrows) in both graphs, with a mean frequency peak at 2.5 kHz in the child and 3.2 kHz in the mother. The right-ear graph is shown for both subjects. (y-axis: sound intensity, dB SPL; x-axis: sound frequency, kHz).

	RESULTS

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A multiple comparison between children with the IUGR variant and controls is shown in the Table 1. The children belonging to the IUGR-variant group showed a significant female predominance (P = .0226), a lower proportion of maternal pregnancy-induced hypertension/preeclampsia (P < .0001), and a higher head circumference (P < .0001), whereas no statistically significant differences were present regarding age at examination, gestational age at birth, history of maternal SGA, percentiles for height and weight at examination, birth weight, and birth length (P .4991).

Nonfunctional PCoAs showed postcompression values in the ipsilateral PCA (mean ± SD) of a 4.34% ± 5.98% increase over basal values (range: 0%–11.27%) vs functional PCoAs with a 76.96% ± 26.89% increase over baseline (range: 23.12%–119.06%). A statistically significant excess of bilaterally nonfunctioning PCoAs was observed both in the children with the IUGR variant (P < .0001) and their mothers (26 of 27 [96.3%] vs 0 of 50 [0%]; P < .0001) as compared with the control groups (Table 1). No significant differences were evidenced regarding the fathers (P .8200; data not shown).

Significantly increased proportions of joint hypermobility and skin softness were observed in the IUGR-variant children as compared with control subjects (P < .0001; Table 1). On the other hand, no significant differences were observed concerning articular mobility and skin examination for the parental groups (P .6515; data not shown), and none of the examined SGA-variant children showed abnormal skin laxity.

All of the children with the IUGR variant and their mothers showed evidence of bilateral DPOAEs notches (Fig 2) as compared with none of the control subjects (P < .0001), with an associated reduction of the AUC in both the IUGR-variant children (P < .0001; see Table 1) and their mothers (AUC right ear: 19.05 ± 18.86 dB of sound pressure level, SPL, vs 48.17 ± 13.41 dB SPL, P < .0001; AUC left ear: 15.11 ± 13.53 dB SPL vs 58.12 ± 18.77 dB SPL, P < .0001). However, the peak frequency of the notches for the variant IUGR children was significantly lower than that of their mothers (2.63 ± 0.39 kHz vs 3.21 ± 0.27 kHz, P < .0001). No significant DPOAE differences were evidenced regarding the fathers (P .6611; data not shown). Likelihoods of random association for the described features in individual children and child-mother pairs were estimated to be 2.25 x 10^–8, and 1.35 x 10^–9, respectively.

	DISCUSSION

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Our findings suggest the presence of a previously unrecognized phenotype in a subset of IUGR/SGA children, based on the following: (1) abnormal auricle shape, related to a minor developmental defect of the helix; (2) bilaterally low hemodynamic responses of the PCoAs; (3) bilateral subclinical cochlear dysfunction; (4) excessively soft skin; and (5) joint hypermobility. In addition, the described IUGR/SGA variant was found to be associated with distinct maternal phenotypic features, including auricle shape changes, transcranial color-coded duplex ultrasonography evidence of bilaterally nonfunctional PCoAs, and subclinical bilateral cochlear dysfunction. The order of magnitude (10^–8 to 10^–9) estimated for a random association of the described signs would theoretically justify a new clinical entity. Given that the follow-up was systematic, without previous subject selection, it is unlikely that selection criteria could potentially affect data interpretation. However, given that intrauterine mortality for this variant remains unknown, an inevitable selection bias could theoretically be present.

Formation of the external ear is a very complex process, and its careful examination and detailed description may prove to be of diagnostic value in specific syndromes.^25,26 The auricle appears early during embryogenesis, developing from the first and second pharyngeal arches, and can be impacted by any disruptions of its development, as well as by the effects of the intrauterine environment.²⁷ Although a statistical relationship between abnormal external ear geometry and IUGR/SGA had been suggested previously by our group,²⁸ the present study indicates that a variant auricle shape is associated with a complex phenotype, thus identifying a previously unrecognized IUGR subset. At this stage of our study, inner ear imaging was not performed. As a consequence, cochlear malformations cannot be ruled out in this particular IUGR/SGA subgroup. However, inner ear congenital malformations are usually found in patients with syndromic sensorineural hearing loss, such as Pendred syndrome,^29,30 although exceptions are known to exist. In particular, patients with complex of enlarged vestibular aqueduct, Mondini dysplasia, large vestibule, and semicircular canal dysplasia usually present with fluctuating hearing loss (93%).³¹ This was obviously not the case in our described SGA-variant phenotype, whereas the hearing "abnormality" observed in our SGA-variant subjects, that is, the presence of notches at DPOAEs, was subclinical at the time of examination.

As the pharyngeal arches develop during the fourth week, they are supplied by arteries, the aortic arches, and the distal parts of the third pair of aortic arches join with the dorsal aortae to form the internal carotid arteries, which supply the ears, orbits, and brain. The PCoAs arise from the dorsal aspect of the intracranial internal carotid artery, run caudally and medially, and, finally, join to the PCA, forming an important connection between the carotid and vertebrobasilar circulations.^32,33 Therefore, the associated abnormalities of the external ear and the PCoAs could be considered as the result of an aberrant development of the mesoderm of the pharyngeal arches.

The occurrence of notches at the DPOAEs in children with the phenotypical SGA variant indicates a subclinical impairment of the outer hair cell function. The mean peak frequencies of the notch at middle-high frequencies in both children with the IUGR/SGA variant and their mothers are compatible with a subclinical dysfunction of the intermediate-basal gyrus of the cochlea. The internal ear develops in the fourth week from the surface ectoderm: the hair cells are specified from the simple epithelium of the early otic vesicle, deriving probably from the same common progenitor of the supporting cells through appropriate cell-cell contacts.³⁴ Thus, the subclinical cochlear dysfunction here observed may likely reflect a primary disturbance of these mechanosensory cells.

The observed changes in skin texture, associated with increased skin softness and macroscopic changes in the stratum corneum, add to previous findings of subtle, permanent skin markers in children with a history of impaired fetal growth. In particular, a relationship among IUGR, fingerprints pattern abnormalities, shape of the palm, and hypertension had been reported previously.⁵ On the other hand, joint hypermobility, a common benign condition (10%–15% in the Western population) of unknown pathogenesis³⁵ has been related previously to infantile hypertrophic pyloric stenosis,³⁶ as well as to genetic disorders involving the extracellular matrix (ECM).³⁷ The coexistence of joint hypermobility and skin abnormalities in SGA children with nonfunctional PCoAs suggests a possible involvement of ECM, although at this stage there is no definite proof for either a previously recognized or undescribed collagen disorder in this subgroup of SGA subjects.

The relatively spared head growth at birth shown by the SGA-variant subjects suggests a form of "primary" IUGR as opposed to the IUGR mostly "secondary" to maternal pregnancy-induced hypertension/preeclampsia of the control group. As a consequence, IUGR should be considered as an adverse effect by a fetoplacental pathology on the intrauterine growth for a fetus with a normal growth target as opposed to a preprogrammed lower size in the "primary" (ie, variant) form described here. By contrast, the observed female prevalence and the close similarity between some of the phenotypical features of SGA-variant children and those of their mothers (ie, auricle helix change, low hemodynamical responses of the PCoAs, and subclinical cochlear dysfunction) remain unexplained at this time, while raising the possibility of inherited traits.

Considering all of these features, the phenotype of the described IUGR/SGA variant is likely the consequence of a large, developmental disturbance occurring early in embryogenesis. In addition, it should be noted that this multiple developmental disorder seems to be generally benign, although no data exist on the intrauterine mortality rate in the proposed phenotypical variant. If we consider the skin, reciprocal epithelial-mesenchymal interactions could coordinate a common developmental program, and its disturbance can determine disorders with defects in multiple organs (ie, pleiotropy). In this context, the ECM could play a primary role, containing a diversity of molecules interacting with each other, as well as with epithelial and mesenchymal cells via specific cell-surface molecules (integrins).

The precise molecular defects underlying the observed clinical phenotype are difficult to be predicted at this stage of knowledge. In IUGR complex genetic mechanisms, such as uniparental disomy³⁸ or epigenetic changes³⁹ seem to be involved in generating different subtypes. In our series, the absence of familial cases makes it unlikely a single gene/monogenic Mendelian inheritance model, whereas suggesting the role of more complex genetic/environmental mechanisms in determining phenotypic features. The use of new, more refined molecular investigation techniques, such as comparative genomic hybridization genomics and telomeric array, could provide interesting clues for a better understanding molecular pathogenesis of the condition described in our patients. Additional studies are also needed to explore the frequency and geographic distribution of the observed IUGR/SGA variant, as well as its possible relationships with long-term prognosis and other possible markers of fetal programming.

	ACKNOWLEDGMENTS

 
We sincerely thank Laura DeFelice and Professors Umberto Simeoni and Tommaso Renieri for helpful suggestions, inspiring discussions, and critical reading of the article; Dr Salvatore Schiavone and Elisa Scalacci for help with data collection; Roberto Faleri and Ombretta Bugiani (Central Library, University Medical School, Siena, Italy) for online research assistance; and all of the IUGR/small-for-gestational-age families for kindly and actively participating in this study.

	FOOTNOTES

 
Accepted Oct 23, 2006.

Address correspondence to Claudio DeFelice, MD, Neonatal Intensive Care Unit, Division of Neonatology, Azienda Ospedaliera Universitaria Senese "Le Scotte" Hospital, Viale M. Bracci 16, 53100 Siena, Italy. E-mail: defelice.claudio{at}libero.it

The authors have indicated they have no financial relationships relevant to this article to disclose.

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