Clinical characteristics.

ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, and syndactyly), elbow and knee flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), and craniofacial abnormalities (which can include bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, and underdeveloped ala nasi), ear malformation, and corneal opacities. Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected pregnancies and newborns; mildly affected individuals may survive to adulthood.

Diagnosis/testing.

The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings by identification of either biallelic pathogenic variants in ESCO2 by molecular genetic testing or premature centromere separation (PCS) by cytogenetic testing.

Management.

Treatment of manifestations: Individualized treatment aimed to improve quality of life; surgery for cleft lip and/or palate, for correction of limb abnormalities, and to improve proper development of the prehensile hand grasp. Prostheses, speech assessment and therapy, special education for developmental delays, and standard treatment for ophthalmologic, cardiac, and renal abnormalities as indicated.

Surveillance: Periodic assessment of: growth and weight gain; motor and language development; speech development and hearing (in those with cleft lip and palate); and educational needs. Follow up for ophthalmologic, cardiac, and/or renal anomalies per treating physicians.

Genetic counseling.

ESCO2 spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ESCO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. When the ESCO2 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

ESCO2 spectrum disorder should be suspected in an individual with the following clinical findings and family history.

Clinical findings [Hennekam et al 2010, Vega et al 2010, Vega et al 2016]:

• Prenatal growth restriction ranging from mild to severe. Mean birth length and weight is below the third centile in most term and prematurely born affected infants.
• Limb malformations including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening. Upper limbs are more severely affected than lower limbs.
• Hand abnormalities. Most commonly oligodactyly with thumb aplasia or hypoplasia, followed by fifth finger clinodactyly or hypoplasia
• Flexion contractures of the knees, ankles, wrists, and elbows; talipes equinovarus
• Craniofacial abnormalities including bilateral cleft lip and/or palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformation
• Developmental delay / intellectual disability is not always present, segregates by families, and probably correlates with the presence of corneal opacities. There are families with severe phocomelia and bilateral cleft lip and palate with no corneal opacities and no intellectual disability. When present, intellectual disability ranges from mild to severe.
• Other
  • Urogenital abnormalities: cryptorchidism, enlarged phallus
  • Renal anomalies: horseshoe kidney, polycystic kidney
  • Heart defects: ventricular septal defect
  • Eye abnormalities: corneal opacities
  • Sparse hair

Family history consistent with autosomal recessive inheritance, including consanguinity

Establishing the Diagnosis

The diagnosis ESCO2 spectrum disorder is established in a proband with suggestive clinical findings by identification of either biallelic pathogenic variants in ESCO2 by molecular genetic testing (see Table 1) or premature centromere separation (PCS) by cytogenetic testing.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ESCO2 spectrum disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ESCO2 spectrum disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

Comprehensive genomic testing. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis; however, to date such variants have not been identified as a cause of ESCO2 spectrum disorder.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ESCO2 Spectrum Disorder

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Gene 1	Method	Proportion of Pathogenic Variants 2 Detectable by Method
ESCO2	Sequence analysis 3	100% 4
	Gene-targeted deletion/duplication analysis 5	None reported 6

1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from subscription-based professional version of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Cytogenetic testing. Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosome abnormality of premature centromere separation (PCS) and separation of the heterochromatic regions (also termed heterochromatin repulsion [HR]) in most chromosomes in all metaphases (Figure 1).

Figure 1.

C-banding of metaphase chromosomes. Arrows show selected chromosomes with premature centromere separation. Solid black arrowhead points to "splitting" of the Y chromosome heterochromatic region. Open arrowheads show selected chromosomes with normal C-banded (more...)

Note on terminology used in RBS: The centromere and the heterochromatin are affected in RBS. (1) The term "premature centromere separation" (PCS) describes the cytogenetic abnormalities observed in standard cytogenetic preparations and the prematurely separating centromeres during metaphase rather than in anaphase. PCS is related to the most probable pathologic mechanism and associated spindle checkpoint activation and impaired cell proliferation. (2) The term "heterochromatin repulsion" (HR) only describes the cytogenetic abnormality of the heterochromatin and does not describe the abnormal process of sister chromatid cohesion, which is fundamental to the pathophysiology of RBS. (3) Until a better term is available to define the structural and functional characteristics of RBS, the authors prefer to use the combined term "PCS/HR."

• 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.
• The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.

Note: PCS/HR is different from premature sister chromatid separation (PSCS) described in Cornelia de Lange syndrome and premature centromere division (PCD) associated with mosaic variegated aneuploidy syndrome, in which separation and splaying involves not only the centromeric regions but also the entire sister chromatids [Plaja et al 2001, Kaur et al 2005].

Aneuploidy, micronucleation, and multilobulated nuclei are also common findings in RBS cell cultures.

Clinical Description

ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening), hand anomalies, multiple joint contractures, craniofacial abnormalities, and often corneal opacities. Intellectual disability is common.

To date 150 individuals have been identified with ESCO2 spectrum disorder [Ismail et al 2016]. The following description of the phenotypic features associated with this condition is based on that report and on Vega et al [2010] and Vega et al [2016].

Growth restriction of prenatal onset is the most consistent finding in all affected individuals. Postnatal growth restriction can be moderate to severe and correlates with the severity of the limb and craniofacial malformations.

Limb malformations include symmetric mesomelic shortening and anterior-posterior axis involvement in which the frequency and degree of involvement of long bones is, in decreasing order:

• Upper limbs. Radii, ulnae, and humeri in the upper limbs;
• Lower limbs: Fibulae, tibiae, and femur.

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

Hand malformations include brachydactyly and oligodactyly. The thumb is most often affected by proximal positioning or digitalization, hypoplasia, or agenesis. The fifth finger is the next most affected digit with clinodactyly, hypoplasia, or agenesis. In those with severe involvement, only three fingers are present (and rarely, only one finger).

Limb bone fusions, evident in individuals with mild phocomelia, are more common in the knees and ankles, although also present in hands.

Craniofacial abnormalities include: cleft lip and/or cleft palate, premaxillary prominence, micrognathia (77%), microcephaly, brachycephaly (63%), midfacial capillary hemangioma (71%), malar flattening (88%), downslanted palpebral fissures (57%), widely spaced eyes (85%), exophthalmos resulting from shallow orbits (59%), corneal opacities (33%), underdeveloped ala nasi (77%), convex nasal ridge, and ear malformations (69%).

Mildly affected individuals have no palatal abnormalities or only a high-arched palate. The most severely affected individuals have fronto-ethmoid-nasal-maxillary encephalocele.

Correlation between the degree of limb and facial involvement is observed: individuals with mild limb abnormalities also have mild craniofacial malformations, whereas those with severely affected limbs have extensive craniofacial abnormalities.

Intellectual disability is present in the majority of affected individuals; normal intellectual and social development have also been reported [Petrinelli et al 1984, Stanley et al 1988, Maserati et al 1991, Holden et al 1992].

Other findings that may be observed:

• Abnormal genitalia
  • Males. Enlarged penis (30%), relatively large appearance in relation to the reduced limbs; cryptorchidism, and hypospadias [Satar et al 1994]
  • Females. Enlarged clitoris (46%)
• Renal anomalies. Polycystic kidney (2%), horseshoe kidney, hydronephrosis (2%)
• Heart defects. Atrial septal defect, ventricular septal defect, patent ductus arteriosus
• Eye abnormalities. Commonly, corneal opacities with occasional involvement of the crystalline lens; other ocular findings include microphthalmia and glaucoma [Ismail et al 2016].
• Hair. Sparse hair, silvery blonde scalp hair
• Cranial nerve paralysis. Occasional; two patients have had third cranial nerve paralysis related to cavernous angioma [Ogilvy et al 1993]; additional extracranial neoplasms have been reported (1 case with malignant melanoma, 1 with rhabdomyosarcoma) [Parry et al 1986, Wenger et al 1988, Feingold 1992].
• Moyamoya disease (2%) and stroke secondary to intracranial aneurysms (4%) occurred during late adolescence and young adulthood [Herrmann et al 1969, Vega et al 2010].

Prognosis. Little is known about the natural history of ESCO2 spectrum disorder. Wide clinical variability is observed among affected individuals, including sibs. The prognosis depends on the malformations present: the severity of manifestations correlates with survival. Mortality is high among most of the severely affected pregnancies and newborns. Mildly affected children are more likely to survive to adulthood.

The cause of death has not been reported for most affected individuals. Reported causes are infection (5 individuals), aneurysm/hemorrhage (3 individuals), and malignancy (3 individuals) [Herrmann & Opitz 1977, Vega et al 2010]. Perinatal mortality is correlated with severity of the malformations; early death is usually secondary to respiratory complications and infection [Van Den Berg & Francke 1993].

Genotype-Phenotype Correlations

To date, correlation of ESCO2 variants with specific phenotypic features has not been established.

Nomenclature

In 1919, John B Roberts reported phocomelia, bilateral cleft lip and cleft palate, and protrusion of the intermaxillary region in three children of an Italian couple who were first cousins [Roberts 1919].

In 1969, J Herrmann and colleagues described a syndrome of intrauterine and postnatal growth retardation, mild symmetric reduction of the limbs, flexion contractures of various joints, multiple minor anomalies (including capillary hemangiomas of the face, cloudy corneas, hypoplastic cartilages of the ears and nose, micrognathia, and scanty, silvery-blond hair), and autosomal recessive inheritance. They named this condition the pseudothalidomide or SC syndrome (for the initials of the surnames of the 2 families described) [Herrmann et al 1969].

Clinical evidence that these two phenotypes are allelic was supported by the observations that both were caused by biallelic pathogenic variants in ESCO2 [Schüle et al 2005, Vega et al 2005].

Other synonyms used for Roberts syndrome in the past are Appelt-Gerken-Lenz syndrome, hypomelia-hypotrichosis-facial hemangioma syndrome, tetraphocomelia-cleft palate syndrome, and pseudothalidomide syndrome.

Prevalence

ESCO2 spectrum disorder is rare; no accurate estimates of prevalence have been published. Approximately 150 individuals of diverse racial and ethnic backgrounds have been reported.

Parental consanguinity is common.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ESCO2 spectrum disorder the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Note: No published guidelines to evaluate the clinical manifestations contributing to morbidity and mortality exist. The recommendations given are based on the literature and the experience of clinical geneticists.