*  Director of Imaging Diagnosis Department, Maternal Tudu Hospital, 284 Cong Quynh St Dist 1, Hochimin City, Vietnam;
** Fécamp, France.

Definition

Roberts syndrome is a rare autosomal recessive developmental disorder, characterized by multiple malformations, in particular symmetrical limb reduction, craniofacial anomalies and growth retardation [3,18,20,21,22].

Synonyms

Roberts syndrome is also known as: Roberts-SC phocomelia syndrome; Pseudothalidomide syndrome; Roberts-SC (pseudothalidomide); SC-phocomelia syndrome; SC syndrome; Hypomelia-hypotrichosis-facial hemangioma syndrome; Appelt-Gerken-Lenz syndrome [1,3,15,23,30]. In all the above synonyms, SC represent the initials of the two affected families where was the syndrome described for the first time [3]. When initially described in 1974 by Herrmann, pseudo-thalidomide or SC syndrome were thought to be distinct entities. Nowadays they are known to be a phenotypic variation of the Roberts syndrome [3].

History

The syndrome was initially described by John Roberts in 1919 and later reviewed by Appelt [2,3,30], but already in 1672, François Bouchard reported an autopsy of an infant with tetraphocomelia, bilateral cleft lip, abnormal fingers, hydrocephalus, micrognathia, and cryptorchidism and consistent with a Roberts syndrome [7]. Furthermore an unlabelled specimen from the Virchow Museum dated to 1898, and exhibiting tetraphocomelia with bilaterally cleft lip, was also later designated as the “Roberts syndrome" [10].

Incidence

The true incidence of the Roberts syndrome is unknown [3].

Case report

The following images show an example of Roberts syndrome. The images represent a combination of two cases of the Roberts syndrome diagnosed in our department.

Images 1, 2: The images show flat fetal profile with micrognathia and retrognathia.

Images 3, 4: The image 3 shows normal fetal head circumference with normal intracranial architecture and femur shortening. The image 4 shows fetal phocomelia.

Images 5, 6: The images show fetal phocomelia.

Images 7, 8: The image 7 shows transverse scan at the level of the fetal eye with slight hypertelorism. The image 8 shows fetal foot with "sandal gap".

Images 9, 10: The image 9 shows a four-chamber view of the fetal heart with atrioventricular septal defect. The image 10 represents 3D scan of the fetal face, showing micrognathia and retrognathia. Note that no cleft lip was present.

Images 11, 12: The image 11 represents 3D scan of the fetal face, showing micrognathia and retrognathia. The image 12 shows 3D scan of the upper fetal extremity with phocomelia.

Images 13, 14, 15, and 16: Postmortem images of the neonates affected by Roberts syndrome.

Diagnostic features

The diagnosis of the Roberts syndrome can be suspected when the following anomalies are observed (note that there is a wide range of severity of malformations among the affected individuals, including siblings [1,5,12]):

• Growth retardation: ranging from mild to severe. Prenatal growth retardation is the most consistent finding in all affected fetuses. Mean birth length and weight is below the third percentile in most term and prematurely-born affected infants [1]. Postnatal growth retardation can be moderate to severe and correlates with the severity of the limb and craniofacial malformations [1,3,8,12,14,15,18,23].
• Limb malformations: bilateral symmetric tetraphocomelia or hypomelia caused by symmetric mesomelic shortening and anterior-posterior axis involvement. The frequency and degree of involvement of long bones is, in decreasing order: radii, ulnae, and humeri in the upper limbs; fibulae, tibiae, and femurs in the lower limbs [1,3,6,8,12,14,15]. However, the limb reduction can be asymmetrical [5,23].

The degree of the limb abnormalities follows a cephalo-caudal pattern: the upper limbs are more severely affected than the lower ones, with several cases of only upper limbs malformations [1].

The hand malformations essentially affect the thumb (proximal positioning, aplasia or hypoplasia). The fifth finger is the next most affected digit with clinodactyly, hypoplasia, or agenesis. Other observed anomalies are: syndactyly, clinodactyly, brachydactyly and oligodactyly. Severe cases can have only three fingers and, rarely, only one finger [1,3].
Elbow or knee flexion contractures and clubfeet have also been reported [1,12,14,17,23,32].

• Craniofacial abnormalities: unilateral, bilateral or median cleft lip and/or palate, premaxillary protrusion,  micrognathia, hypertelorism, microbrachycephaly, exophthalmos, downslanting palpebral fissures, corneal opacities, coloboma, cataract, malar hypoplasia, midfacial capillary hemangioma, hypoplastic nasal alae, beaked nose, wide nasal bridge, delayed eruption of permanent teeth and ear malformation such as dysplastic or  hypoplastic ears [1,3,6,8,12,14,17,23]. Mildly affected individuals could have no palatal abnormalities or only a high-arched palate [1]. The most severely affected individuals have fronto-ethmoid-nasal-maxillary encephalocele such as the draw below [1]. A strict correlation is observed between the degree of limb and facial involvement [1].

Other abnormalities:

• Heart. Atrial septal defect, ventricular septal defect, patent ductus arteriosus, aneurysm of the interatrial septum without hemodynamic significance [1,3,4].
• Kidneys. Polycystic kidneys, horseshoe kidney, dysplastic kidneys [1,3,23].
• Male genitalia. Enlarged penis (relatively large appearance in relation to the reduced limbs),  hypospadias,  cryptorchidism, hypogonadism [1, 3,14,17,23].
• Female genitalia. Enlarged clitoris, ovarian dysgenesis, hypogonadism [1,19,23].
• Hair. Sparse hair, silvery blonde scalp hair [1,23].
• Cranial nerve paralysis. Lack of the swallowing reflex [1,4].
• Moyamoya disease [1].
• Simian crease [17].
• Stroke [1].
• Gastrointestinal abnormalities. Obstructions, rudimentary gallbladder, accessory spleen have been described [3,8].
• Oligohydramnios [3].
• Intellectual ability. Mental retardation is present in the majority of affected individuals. However, normal intellectual and social development have been reported [1,8].

These, usually marked anomalies, make the ultrasonographic detection of the Roberts syndrome relatively easily recognizable.

Cytogenetic fetures

The diagnosis of the Roberts syndrome relies on cytogenetic testing [1]. Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the following findings:

1. Characteristic chromosomal abnormality is premature centromere separation (PCS), which describes the prematurely separated centromeres during metaphase and separation of the heterochromatic regions, also termed heterochromatin repulsion (HR). These anomalies are found  in most chromosomes [1,2,8,12,14,20,26,31]. These aspects are most prominently observed at certain regions in which the chromatin is composed of highly reiterated base sequences [11]. The observed abnormalities are interpreted as evidence for the presence of a genetically determined disturbance affecting the normal mechanisms for pairing and disjoining of sister chromatids [11].

2. Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers [1,3].

3. The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads [1,20,26].

4. Aneuploidy, micronucleation and multilobulated nuclei are also common findings in Roberts syndrome’s cell cultures [1,2,20].

Carrier status cannot be determined by cytogenetic analysis [1,25]. Carrier testing of at-risk relatives may be available from laboratories offering clinical confirmation of mutations identified in research labs if the mutations have been identified in the family [1]. There is no correlation between the phenotypical severity of the Roberts syndrome and the importance of the cytogenetical changes [25].
In front of suggesting anomalies, cytogenic analysis of fetal cells, obtained from chorionic villi sample, amniocentesis or cordocentesis is required to confirm the diagnosis prenatally. The presence of premature centromere separation makes the diagnosis. But a negative cytogenetic analysis does not exclude Roberts syndrome [27,28]. In those cases, a second analysis using a different type of fetal tissue is required [3].
Note: the cytogenetical anomalies observed in Roberts syndrome are different from premature sister chromatid separation (PSCS) described in Cornelia de Lange syndrome and  from premature centromere division (PCD) associated with mosaic variegated aneuploidy syndrome that are differential diagnosises [1].

Molecular genetic

The gene ESCO2 is the main gene with documented Roberts syndrome-causing mutations. It is is located on 8p21.1 locus [1,33]. The protein produce by the ESCO2 gene is required for the establishment of sister chromatid cohesion during S phase [26]. Sequence analysis of the ESCO2 gene is available on a research basis only [1]. Furthermore, some others genes have been suspected for being responsible of Roberts syndrome [21]. To date, no other phenotypes have been associated with mutations in ESCO2 [1].
In April 2008, there were 26 known mutations of the ESCO2 gene [13].

Normal gene product. Translation of the mRNA results in a protein with two different domains, the C-terminal portion with acetyltransferase activity and the N-terminal end, which binds to chromatin [1].

Abnormal gene product. The abnormalities reported in the ESCO2 gene are predicted to lead to loss of function, truncation in the protein, or amino acid changes The cellular phenotype resulting from this missense mutation is equivalent to the one produced by nonsense and frameshift mutations, indicating that the Roberts syndrome molecular mechanism involves loss of acetyltransferase activity [13]. Alterations in ESCO2 function result in lack of cohesion at heterochromatic regions, which may lead to activation of the mitotic spindle checkpoint with the subsequent mitotic delay and the impaired cell proliferation observed in RBS cells [1,13].

Differential diagnosis

While some syndromes share some of the clinical features of Roberts syndrome (RBS), a physical examination and skeletal survey followed by the finding of cytogenetic abnormalities should allow for differentiation between individuals with RBS and those with conditions that are clinically similar [1].

1) In cases of mild manifestations, syndromes with associated preaxial reduction defects to be considered in the differential diagnosis include the following:

• Baller-Gerold syndrome, characterized by [1]:
  • Autosomal recessive inheritance.
  • Coronal craniosynostosis with ocular proptosis and bulging forehead.
  • Radial ray defect, manifest as oligodactyly, aplasia or hypoplasia of the thumb and radius.
  • Growth retardation and poikiloderma.
• Fanconi anemia, characterized by [1]:
  • Autosomal recessive inheritance.
  • Short stature.
  • Abnormal skin pigmentation.
  • Malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system, hearing loss, hypogonadism and developmental delay.

2) In cases of severe manifestations, the following syndromes should be considered in the differential diagnosis:

• Thrombocytopenia-absent radius (TAR) syndrome, characterized by [1]:
  • Autosomal recessive inheritance.
  • Bilateral absence of the radii and thrombocytopenia.
  • Lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved.
  • The presence of cleft lip and palate associated with skeletal changes such as absent radius suggests RBS rather than TAR syndrome.
• Tetra-amelia, X-linked (Zimmer tetraphocomelia) characterized by [1]:
  • Tetra-amelia.
  • Facial clefts.
  • Absence of ears and nose.
  • Anal atresia.
  • Other findings include absence of frontal bones, pulmonary hypoplasia with adenomatoid malformation, absence of thyroid, dysplastic kidneys, gallbladder, spleen, uterus, and ovaries, and imperforate vagina.
• Tetra-amelia, autosomal recessive characterized by [1]:
  • Amelia.
  • Severe lung hypoplasia and aplasia of the peripheral pulmonary vessels.
  • Cleft lip/palate.
  • Hypoplasia of the pelvis: malformed uterus, atresia of the urethra, vagina, and anus.
  • Diaphragmatic defect.
  • Agenesis of the kidney, spleen, and adrenal glands.
• Splenogonadal fusion with limb defects and micrognathia, characterized by [1]:
  • Autosomal dominant inheritance.
  • Abnormal fusion between the spleen and the gonad or the remnants of the mesonephros.
  • Tetramelia.
  • Mild mandibular and oral abnormalities (micrognathia, multiple unerupted teeth, crowding of the upper incisors and deep, narrow, V-shaped palate without cleft).
• DK phocomelia syndrome, characterized by [1]:
  • Autosomal recessive inheritance.
  • Phocomelia.
  • Thrombocytopenia.
  • Encephalocele.
  • Urogenital abnormalities.
  • Additional malformations include: cleft palate, absence of radius and digits, anal atresia, abnormal lobation of the lungs, and diaphragmatic agenesis.
• Holt-Oram syndrome, characterized by [1]:
  • Autosomal dominant inheritance.
  • Upper-extremity malformations involving radial, thenar, or carpal bones.
  • Congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum.
  • Cardiac conduction disease.
  • Occasionally, phocomelia is observed.
• Thalidomide embryopathy, characterized by [1]:
  • Abnormalities of the long bones of the extremities. Upper limb bones are affected in an order of frequency starting with the thumb, followed by the radius, the humerus, the ulna, and finally the fingers on the ulnar side of the hand. In extreme cases, the radius, ulna, and humerus are lacking; and the hand bud arises from the shoulders. Legs may be affected but less severely.
  • Ears malformations (anotia, microtia,  accessory auricles).
  • Eyes malformations (coloboma of the iris, anophthalmia, microphthalmia).
  • Internal defects commonly involve the heart, kidneys, and urinary, alimentary, and genital tracts.

First introduced as a sedative agent, thalidomide was also used to treat morning sickness. It was withdrawn from the market in the 1960s because of reports of teratogenicity. Currently, thalidomide is used to treat various cancers and dermatologic, neurologic, and inflammatory diseases [1].

3) Disorders with similar but not the same cytogenetic findings include the following:

• Cornelia de Lange syndrome, characterized by [1]:
  • Autosomal dominant or X-linked inheritance.
  • Distinctive facial features.
  • Growth retardation.
  • Hirsutism.
  • Upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly.
  • Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly.
  • Frequent findings include cardiac septal defects, gastrointestinal dysfunction, and cryptorchidism or hypoplastic genitalia.

Cytogenetic findings include premature sister chromatid separation (PSCS), in which separation and splaying involves not only the centromeric regions but also the entire sister chromatids [1].

• Mosaic variegated aneuploidy syndrome, characterized by [1]:
  • Autosomal recessive inheritance.
  • Severe microcephaly.
  • Growth deficiency.
  • Mental retardation.
  • Childhood cancer predisposition.
  • Constitutional mosaicism for chromosomal gains and losses.

Cytogenetic findings include premature centromere division (PCD), in which mitotic cells show split centromeres and splayed chromatids in all or most chromosomes.

Prenatal diagnosis

Prenatal diagnosis for at-risk pregnancies requires repeated ultrasound examinations combined with cytogenetic testing [1].

• Ultrasound examination. Because of the often marked anomalies, the sonographic pre-natal diagnosis of the Roberts syndrome is easy and possible as soon as 12 weeks [1,20,24]. Confirmation of the suspected diagnosis necessits cytogenetic testing [1].
• Cytogenetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by cytogenetic testing of fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks" gestation or chorionic villus sampling  at approximately 11 to 12 weeks of gestation.
• Molecular genetic testing. The molecular genetic testing for prenatal diagnosis of Roberts syndrome is not available in routine. However, prenatal testing may be available for families in which the disease-causing mutation has been identified [1].

Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified [1].

Genetic counseling

Mode of inheritance:

The rare Roberts syndrome (RBS) is inherited in an autosomal recessive manner with marked variability of phenotypic expression [1,4,3,5,8,13,14,19,23]. As all the genopathies, the Roberts syndrome could affect several members of a family or twins [16,19,29]. The sex-ratio is logically 1:1 [12].

Risk to family members:

Parents of a proband

• The parents of an affected child are obligate heterozygotes (carriers of one mutant allele) [1]. As usual in autosomal recessive pathologies, heterozygotes individual also called carriers are asymptomatics [1].

Sibs of a proband

• At conception, each sib of an affected fetus has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected (not  a carrier) [1,3,4].

Offspring of a proband

• Pregnancies in affected individuals are rare. However, two have been reported in 1986 [1]. The offspring of an individual with RBS are obligate heterozygotes (carriers) [1].

Other family members of a proband

• Each sib of the proband"s parents is at a 50% risk of being a carrier [1].

Prognosis

The prognosis and survival depends on the severity of malformations [1]. So, mortality is high among the most severely affected infants, but mildly affected children are more likely to survive to adulthood. However, survival beyond the infancy is quite infrequent [1,3]. The cause of death has not been reported for most affected individuals [1]. When detected before viability, termination of pregnancy can be offered. After viability, standard obstetrical management is not altered [3].

Postnatal management

Evaluations following initial diagnosis [1]

• Radiographic documentation of the craniofacial, limb, and hand anomalies.
• Orofacial and limb malformation assessment to determine the need for management and plastic surgery.
• Ophthalmologic evaluation.
• Echocardiogram.
• Ultrasound evaluation of the kidneys.
• Multidisciplinary evaluation including psychological assessment and formal, age-appropriate developmental assessment.

Treatment of manifestations [1]

• Surgical treatments including cosmetic or reconstructive surgery.
• Prostheses.
• Intervention and/or special education if developmental delays are detected.
• Standard treatment for specific cardiac defects and renal dysfunction.

Surveillance [1]

• Periodic follow-up to monitor mental and physical growth and to determine if frequent infections are an issue.
• Regular follow-up for assessment of speech and ear infections/hearing loss if cleft lip and palate are present.
• Annual screening for developmental delays or learning disorders.
• Monitoring as per specific ophthalmologic, cardiac, or renal anomalies.

References

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