Prenatal Diagnosis of Robinow Syndrome: A Case Report Simon Castro, MD,1 Efren Peraza, MD,1 Astrid Barraza, MD,2 Marco Zapata, MD1 1
Department of Obstetrics and Gynecology, Hospital General Dr. Norberto Trevi~ no Zapata, Victoria, Tamaulipas, Mexico 2 Department of Genetics, Hospital Infantil de Ciudad Victoria, Tamaulipas, Mexico Received 1 November 2012; accepted 30 August 2013
ABSTRACT: Robinow syndrome, also known as fetal face syndrome, is a rare genetically heterogeneous condition characterized mainly by mesomelic limb shortening, facial malformations, and genital abnormalities. This report describes the sonographic findings in a case of autosomal-dominant Robinow syndrome diagnosed at 23.1 weeks’ gestation, in a patient with no history of affected relatives. Here we describe the sonographic characteristics of this syndrome from the diagnosis until birth. The prenatal and postnatal findings, the differential diagnosis, and the prognosis of patients with this C 2013 Wiley Periodicals, Inc. syndrome are discussed. V J Clin Ultrasound 42:297–300, 2014; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22103 Keywords: Robinow syndrome; fetal face syndrome; prenatal diagnosis; sonography; fetal malformations
obinow syndrome was described for first time in 19691; since then, more than 100 cases have been published in the literature, with both the autosomal-dominant and the autosomal-recessive forms being reported.2,3 The main craniofacial characteristics are macrocephaly, frontal bossing, hypertelorism with prominent eyes, midface hypoplasia, a broad nasal bridge, and micrognathia. These lesions can be seen on prenatal ultrasound (US) examinations. Despite this, there are only three reports of prenatal diagnosis of this syndrome.4–6 Prenatal diagnosis is essential because it allow clinicians to inform parents about the evolution of this condition and the prognosis. We report a
Correspondence to: S. Castro C 2013 Wiley Periodicals, Inc. V
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case of autosomal-dominant Robinow syndrome that was diagnosed prenatally. CASE REPORT
Our patient was a 26-year-old primigravida, single woman who had no family history of consanguinity. During the early weeks of gestation, the mother had consumed alcohol, painkillers, and antibiotics for an unspecified respiratory infection. She also smoked during this period. She underwent a US examination at 23.1 weeks’ gestation. The US examination was performed with a Voluson E8 scanner equipped with an abdominal RAB 4–8 curved-array transducer (GE Healthcare, Milwaukee, WI). It revealed a female fetus in cephalic presentation with fetal biometry consistent with the menstrual age, except for the size of the radius and ulna, which were at the tenth percentile for the gestational age. In addition, the fetus had an abnormal facial profile with flattening of the frontal bone, a broad nasal bridge, micrognathia (Figure 1A); hypertelorism with prominent eyes (Figure 1B and 1C); cleft palate, and low-set ears. The thorax was observed to be narrower in comparison with the abdomen (Figure 1D). The stomach was not visible, but the amount of amniotic fluid was normal. Throughout the study period, we observed abnormal positioning of the lower legs with hyperextension and little mobility. In addition, we also observed syndactyly in the right foot and also probably club foot. A US examination conducted 3 weeks later showed similar findings: the legs remained in hyperextension with limited mobility; the long bones of the forearm were slightly shorter, and this time, we did see the stomach. 297
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FIGURE 1. (A) Sagittal view of the facial profile shows the broad nasal bridge and severe micrognathia. (B) Three-dimensional US rendering of the fetal face shows hypertelorism and prominent eyes. (C) Two-dimensional US image of the fetal face. Note the prominent eyes. (D) Sagittal view of the thorax and abdomen shows a narrow thorax in comparison with the abdomen.
At 32.3 weeks’ gestation, a cesarean section was performed due to severe pre-eclampsia, and a female newborn was delivered. The newborn weighed 1320 g and had an Apgar score of 5 and 8 at 1 and 5 minutes, respectively, height of 37 cm, and gestational age of 33.4 weeks according to Capurro’s method. Newborn screening revealed a large anterior fontanel, hypertelorism with prominent eyes, micrognathia, cleft palate, lowset ears, narrow thorax with 13 ribs, umbilical hernia, clitoral hypoplasia, right foot syndactyly, and a pilonidal cyst. The lower extremities still showed hyperextension and abduction (Figure 2). During the neonatal period, we observed alterations in the swallowing mechanism that required gastrostomy, gastroesophageal reflux grade 3, anemia requiring a single blood transfusion, and hyperbilirubinemia that was managed with phototherapy. The audiological examination reported abnormal results. Genetic analysis revealed the karyotype to be XX. The newborn was discharged because of improvement at 22 days of age. The final diagnosis made by the genetics department was autosomal-dominant Robinow syndrome. At clinical examination at 1 year, the child presented with delayed neuropsychomotor development and generalized hypotonia and could not walk. She also presented typical features of 298
frontal bossing, hypertelorism with prominent eyes, midface hypoplasia, broad nasal bridge, micrognathia, cleft palate, narrow thorax, umbilical hernia, and hypoplastic genitalia. She had short stature (64 cm) and low weight (5270 g) and presented recurrent respiratory infections.
Robinow syndrome is very rare, with the prevalence estimated to be 1 in 500,000 births.7 The ROR2 gene, located on chromosome 9q22, is responsible for the autosomal-recessive form of the disease, with its mutations causing loss of function of a tyrosine kinase that is involved in cellular growth and differentiation.2 Some cases of the autosomal-dominant form are a result of a heterozygous mutation in the gene WNT5A located on chromosome 3p.3 This mutation was described in affected members of the family originally reported by Robinow et al.1 However, the WNT5A mutations have been shown to occur only in a small minority of the patients. Current prenatal genetic diagnosis is not possible because in most cases it is not known which gene or genes are involved. Although the craniofacial, skeletal, and genital abnormalities seen in Robinow syndrome JOURNAL OF CLINICAL ULTRASOUND
PRENATAL DIAGNOSIS OF ROBINOW SYNDROME
FIGURE 2. Photograph of the newborn in which abduction and hyperextension of the lower extremities can be seen.
can be detected during pregnancy by US examination, to the best of our knowledge, only three cases of prenatal diagnosis of this syndrome have been reported. Loverro et al4 reported the first case of autosomal-dominant Robinow syndrome diagnosed at 19 weeks’ gestation in a woman who had a previous child with this syndrome; the diagnosis was based on marked shortening of the long bones of the forearm and an abnormal ulna/humerus length ratio detected by US examination. However, they did not report the craniofacial features of this syndrome. Percin et al5 published another case of autosomal-recessive Robinow syndrome diagnosed at 12.4 weeks’ gestation based on the presence of a nuchal translucency of 3.2 mm and femur and humerus lengths that were smaller than expected for the given gestational age. The mother was of Turkish origin, in a nonconsanguineous marriage, and had had a child affected with this condition.5 However, in that case, pregnancy was terminated. A third case of autosomal-recessive Robinow syndrome was reported by Guven et al6 in a Turkish woman at 33 weeks’ gestation. The woman was in a consanguineous marriage and did not have other children with this condition. Prenatal US examination revealed a decrease in the lengths of both the humerus and the femur, and shortening of the long bones of the forearm, along with frontal bossing, mild hypertelorism, reduced thoracic perimeter, and hemivertebra.6 Unlike in our case, in the case of this newborn the condition was of the autosomal-recessive type; therefore, the phenotypic expression was more severe than that in the autosomaldominant form and, therefore, easier to diagnose prenatally. VOL. 42, NO. 5, JUNE 2014
Differential diagnosis of Robinow syndrome should include differentiation between the autosomal-dominant and -recessive forms, as they share many physical characteristics such as craniofacial, skeletal, and genital malformations. Nevertheless, the characteristics of the recessive form tend to be more severe, and the incidence of vertebral defects, such as hemivertebrae and scoliosis, is much higher.8 The features of Robinow syndrome overlap those of some other malformations. Therefore, these conditions should also be considered in the differential diagnosis. Heterozygous achondroplasia is the most common form of nonlethal skeletal dysplasia; its main US features are macrocephaly, frontal bossing, a depressed nasal bridge, and rhizomelic shortening of the limbs. However, hypertelorism, prominent eyes, and micrognathia, that are characteristic of Robinow syndrome, are not seen in achondroplasia.9,10 Machado et al11 reported a case of Antley-Bixler syndrome in which craniofacial characteristics such as frontal bossing, hypertelorism with proptosis, midfacial hypoplasia, and micrognathia were similar to those in Robinow syndrome. However, craniosynostosis and bowing of the femur and tibia frequently seen in this syndrome are not observed in Robinow syndrome. Another diagnostic possibility is Aarskog syndrome. Sepulveda et al12 published a case in which Aarskog syndrome was diagnosed at 28 weeks’ gestation based on the findings of hypertelorism, short long bones, vertebral defects, and digital anomalies. Unlike Robinow syndrome, this syndrome is not associated with micrognathia, and the presentation of hypertelorism with prominent eyes is more variable. Campomelic dysplasia shares some craniofacial anomalies with Robinow syndrome, such as large anterior fontanelle, hypertelorism, cleft palate, and micrognathia. However, it can be distinguished by the presence of shortening and bowing of the tibia and femur, which is not seen in Robinow syndrome.10 The abnormalities detectable by US examination in the case of Opitz syndrome are a prominent forehead, hypertelorism, cleft lip and palate, and micrognathia. However, unlike Robinow syndrome, this syndrome is not associated with skeletal abnormalities.10 Raine syndrome is an autosomal-recessive condition characterized by frontal bossing, small nose with a hypoplastic nasal bridge, hypertelorism with prominent eyes, low-set ears, micrognathia, and cleft palate. However, osteosclerosis and intracerebral calcifications present in this syndrome are not observed in Robinow syndrome.13 299
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This is the second case of prenatal diagnosis of autosomal-dominant Robinow syndrome reported in the literature and the first to describe the characteristic US craniofacial findings during pregnancy. These characteristics include hypertelorism with prominent eyes that give the impression of exophthalmos, low-set ears, micrognathia, and cleft palate. It is important to highlight the marked hyperextension of the lower extremities observed in the prenatal and neonatal period in this study, as this finding has not been reported previously in Robinow syndrome. Despite the presence of a normal amount of amniotic fluid, we were unable to visualize the stomach in the first US examination. However, we were able to observe the stomach with amniotic fluid on the second US examination obtained 3 weeks later. The observations suggested the presence of a swallowing disorder, which was later observed in the neonatal period. The prognosis of Robinow syndrome, especially the autosomal-dominant form, is generally good. Eighty percent of patients have normal intelligence, but some degree of mental retardation may occur, primarily in the case of the autosomal-recessive form. It carries a 10% risk of mortality, with all childhood deaths reported only in patients with autosomal-recessive Robinow syndrome.14 In conclusion, we report the US findings in a case of Robinow syndrome. In the presence of hypertelorism with prominent eyes, micrognathia, and cleft palate, Robinow syndrome should be included in the differential diagnosis. As both parents were normal and there was no history of affected relatives, we believe that in this case the condition was caused by a de novo mutation. Although no molecular genetic studies were performed, the US characteristics and neonatal findings support the diagnosis of autosomal-dominant Robinow syndrome.
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