A 21-year-old woman in her second pregnancy was referred to our Maternal-Fetal Unit for abnormal fetal growth detected during a 23-week routine scan. Her husband was 29 years old and this baby was his first. There was neither consanguinity nor any family history of congenital anomalies. Fetal detailed ultrasound findings (Accuvix V10, Medison, Seoul, Korea) were cranial suture diastasis (Figure 1a), nasal bone hypoplasia (Figure 1b), cranial bones and clavicles hypomineralization (Figures 1b and c), maxillary hypoplasia (Figure 1d), cerebellar vermis hypoplasia (Figure 2a) and low-set ears (Figure 2b). With this prenatal information the first diagnosis proposal was cleidocranial dysplasia. Karyotype analysis was suggested but impossible to realize due to administrative red tape.
In prenatal ultrasound follow-up an intrauterine growth restriction was identified. At 32 weeks new central nervous system findings were detected: hypoechoic frontal cortex images suggestive of bilateral porencephalic cysts (Figure 2c) and first cervical vertebra dysraphism with dura mater bulging (Figure 2d).
At 35 weeks intrauterine growth restriction and Doppler evaluation defined cesarean section. A male baby of 1410 g and 44 cm height was born. Apgar score was 8 at 1 min and 9 at 5 min. Minor respiratory distress was solved with cephalic oxygen chamber. Anthropometric measurements were cephalic perimeter 29 cm (P<5), 44 cm height (P 10 to 25), inner canthal distance 1.6 cm (P 3), interpupillary distance 3 cm (P<3), outer canthal distance 4.6 cm (P 3 to 50), palpebral fissures 1.2 cm (P<3), labial intercommissure 1.8 cm (P<3), total ear length 2.4 cm (P<3), total hand length 6 cm (P 50 to 97) and middle finger length 2.5 cm (P 50 to 97); lower segment length 19.6 cm, upper segment length 24.4 cm and upper/lower segments ratio 1.24 (normal range 1.65 to 1.70); feet length 7 cm (P 50 to 75) and penis length 1.6 cm (P<3).
Physical examination showed pseudohydrocephalus, hypotricosis, scalp collateral venous system visible, triangular face (Figure 3a), widened fontanelles, biparietal prominence, low-set ears, upper oblique palpebral fissure, depressed nasal bridge with beaked nose profile (Figure 3b). Labial commissures had a downward orientation; two central natal teeth were visible, micrognathia and thin neck were evident. The cardiac evaluation demonstrated a systolic murmur grade II/IV. External genitalia agreed with male condition except for bilateral criptorquidia. Limbs presented general hypotrophy and with imitated articular movements (Figure 3c). Hands and feet were longer than normal (Figure 3d and e). Reduced subcutaneous fat was evident.
Neurological examination reported general hypertonic condition and poor suction.
Echocardiogram showed persistent ductus arteriosus 2.4 mm with mild pulmonary hypertension, without cardiac structural anomalies. Transfontanellar scan demonstrated hypoechoic collection associated with bilateral frontal porencephalic cysts and a wider cisterna magna and a dysraphism of the first cervical vertebra with dura mater bulging. Axial computerized tomography reported hypodense lines suggestive of bilateral frontal porencephalic cysts. All these findings permite to conclude that this case correspond to the Wiedemann–Rautenstrauch syndrome (WRS; online mendelian inheritance in man: 264090) or neonatal progeroid syndrome.1,2
Neonatal respiratory distress was successfully resolved after 24 h. Indirect hiperbilirrubinemia was treated with phototherapy. The baby was discharged once adecuate suction level was reached 40 days after birth weighing 1925 g. At 3 weeks buttocks upper fat was evident.
According to medical literature, WRS is a low frequency genetic condition; 60% of the cases reported are from Colombia,2, 3, 4 which could obey to the following reasons: a geographic variation, misinterpreted diagnosis, unreported cases or only reported in the gray literature.
Common phenotypic characteristics in WRS are pseudohydrocephalus, craniofacial disproportion, reduced subcutaneous fat, thin skin, rigid joints and neonatal teeth.4, 5, 6, 7 Inheritance pattern is known, however, neither the molecular-genetic mechanisms nor the pathophysiology have clearly been established.2,3,6,8, 9, 10, 11 The only paper describing prenatal findings based them on ultrasound biometry; however, these are not specific to the syndrome.12
There are no other medical case reports available that describe prenatal ultrasound images about WRS structural characteristics. Our case report allows prenatal and postnatal images correlations, and improves craniofacial anomalies diagnosis approach. Cranial sutures diastasis, skull and facial bones hypomineralization are fetal key ultrasound findings. They should be considered important in any routine prenatal scan. Furthermore, clavicle hypomineralization is a new finding that we believe deserves to be included in phenotypic new description.
In prenatal ultrasound follow-up, third trimester findings were porencephalic cysts not previously described in either pre- or postnatal WRS case reports. Disorders of the cortical development: microgyria, cortical atrophy and cerebellar atrophy have been associated.1,7 Porencephalic cysts are the final result of brain vascular stroke (ischemia or hemorrhage) that involves gene COL4A1. This condition is multifactorial and we cannot establish whether it is part of WRS or casual unrelated condition associated with WRS.13
Another prenatal finding not previously described is cervical vertebral disraphism with dura mater bulging. Three-dimensional images were helpful in prenatal diagnosis of facial anomalies WRS: low-set ears, upper oblique parpebral fissure and depressed nasal bridge with beaked nose. At 3 weeks of neonatal life fat appeared in the upper buttocks; a typical WRS sign. There is no evolutive description about natural history of upper fat buttocks in WRS and clinical variable expression disease ought to be considered.14
Two patophysiological mechanisms have been described; the first mechanism belongs to the group of progeroid disorders due to defective genomic maintenance leading to loss of cells and impaired replacement of damaged cells. The second mechanism belongs to the group of diseases associated with altered transforming growth factor-β signaling, which plays an important role in the induction of cellular senescence.1,10,11,15
Despite autosomal recessive inherited pattern described for WRS, molecular mechanisms of the disease are not clear. Owing to the similarity of the clinical manifestations with those of Hutchinson–Gilford syndrome (Progeria), LMN A/C gene has been proposed but never confirmed in WRS. Actually, WRS genetic mechanism and physiopathology are still unknown.2,3,6,8, 9, 10, 11
Recently other candidate genes have been proposed. This gene is not specific to WRS, but it is a mechanism that could be considered; this mechanism has been documented in the progeroid variant of Marfan syndrome with FBN1 mutation.15
The phenotype of WRS is distinctive but shows some overlap with other progeroid syndromes, which include Hutchinson–Gilford Progeria, De Barsy syndrome, Cockayne syndrome, Berardinelli–Seip syndrome, Leprechaunism and Hallermann Streiff; however, these syndromes have different ages of presentation and clinical manifestations.16
The precise prenatal diagnosis of craniofacial anomalies remains difficult due to the various genetic alterations, all of them of low prevalence. This article could contribute to a better knowledge of one of them, the WRS. The new findings presented in this article should allow an earlier and more precise diagnosis that would help a multidisciplinary group accompany and advice parents confronted with such pregnancy.
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The authors declare no conflict of interest.
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Becerra, C., Contreras-García, G., Perez Vera, L. et al. Wiedemann–Rautenstrauch syndrome prenatal diagnosis. J Perinatol 34, 954–956 (2014). https://doi.org/10.1038/jp.2014.156
American Journal of Medical Genetics Part A (2017)
American Journal of Medical Genetics Part A (2016)