ESCO2 Spectrum Disorder

Hugo Vega; Miriam Gordillo; Ethylin Wang Jabs

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ESCO2 Spectrum Disorder

Hugo Vega, MD, PhD, Miriam Gordillo, PhD, and Ethylin Wang Jabs, MD.

Author Information and Affiliations

Initial Posting: April 18, 2006; Last Update: August 14, 2025.

Estimated reading time: 31 minutes

Summary

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 of the upper and/or lower limbs), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia), flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations), and ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities). Intellectual disability (ranging from mild to severe) is common VSports注册入口. Early mortality is common among severely affected infants; mildly affected individuals may survive to adulthood.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Individualized treatment to improve quality of life; feeding and nutrition support; management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed; hand surgery as needed to facilitate early development of prehensile grasp and improve motor function; specialized bottle and surgery for cleft lip and/or palate; surgical treatment for craniosynostosis and micrognathia; treatment of ocular issues per ophthalmologist; developmental and educational support including speech therapy; standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities; prompt treatment of infection with management per infectious disease specialist; treatment of stroke per neurologist; treatment of malignancy per oncologist; family and social support.

Surveillance: Assess growth, limb mobility and function, development and educational needs, blood pressure, frequency of infections, and home adaptation needs at each visit; assessment of feeding, speech development, and hearing (in those with cleft lip and palate) per craniofacial team; kidney function tests annually; follow up for ophthalmologic and cardiac anomalies per treating physicians; physical examination including full skin and neurologic examination for evidence of malignancy annually; referral to neurologist including brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities, and/or heart defects; assess for clinical manifestations of aneurysms and vascular malformations annually starting in adolescence; serum immunoglobulin levels in infancy.

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 asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ESCO2 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible VSports. Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination.

GeneReview Scope (V体育官网入口)

ESCO2 Spectrum Disorder: Included Phenotypes
Roberts syndrome SC phocomelia syndrome

: For synonyms and outdated names see Nomenclature.

Diagnosis

ESCO2 spectrum disorder comprises a phenotypic continuum that ranges from Roberts syndrome at the severe end to SC phocomelia syndrome at the milder end.

"VSports app下载" 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 premature 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 with bone synostoses and pterygia; 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 malformations
Eye abnormalities including microphthalmia, nystagmus, glaucoma, and corneal opacities
Developmental delay and/or intellectual disability in some individuals
Urogenital abnormalities such as cryptorchidism, enlarged phallus/clitoris
Heart defects including atrial septal defect, ventricular septal defect, persistent ductus arteriosus
Kidney manifestations such as polycystic kidney, horseshoe kidney, hydronephrosis
Sparse hair
Increased risk of infection

Family history is consistent with "VSports最新版本" autosomal recessive inheritance (e. g. , affected sibs and/or parental consanguinity) V体育安卓版. Absence of a known family history does not preclude the diagnosis.

"V体育官网入口" Establishing the Diagnosis

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

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants VSports最新版本. (2) Identification of biallelic ESCO2 variants of uncertain significance (or of one known ESCO2 pathogenic variant and one ESCO2 variant of uncertain significance) does not establish or rule out the diagnosis.

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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2) V体育平台登录.

Option 1

Single-gene testing. Sequence analysis of ESCO2 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplication; to date, however, such variants have not been identified as a cause of ESCO2 spectrum disorder.

A limb malformation or cleft palate multigene panel that includes ESCO2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Given the rarity of ESCO2 spectrum disorder some panels may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

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

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

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; 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 2020]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Cytogenetic Testing

Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosome abnormality of PCS and separation of the heterochromatic regions (heterochromatin repulsion; HR) in most chromosomes in all metaphases (see 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: The centromere and the heterochromatin are affected in ESCO2 spectrum disorder. (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 ESCO2 spectrum disorder. (3) Until a better term is available to define the structural and functional characteristics of ESCO2 spectrum disorder, 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 Roberts syndrome cell cultures.

V体育官网入口 - Clinical Characteristics

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 ocular manifestations. Intellectual disability is common. To date, 173 individuals have been identified with ESCO2 spectrum disorder. The following description of the phenotypic features associated with this condition is based on these reports [Vega et al 2010, Vega et al 2016].

"V体育安卓版" Table 2.

ESCO2 Spectrum Disorder: Frequency of Select Clinical Features

Feature	% of Individuals w/Feature	Comment
Growth deficiency	95%
Phocomelia	95%	Upper limbs only (21%) Upper & lower limbs (79%)
Microcephaly	81%
Bone fusions	65%	Knees, ankles, wrists, elbows, talipes equinovarus Syndactyly (18%) Flexion contractures (16%)
Cleft lip & palate	47%	Cleft palate only (5%)
Ocular abnormalities	37%	Microphthalmia (48%), nystagmus (48%), glaucoma (48%), corneal opacities (22%)
Developmental delay / intellectual disability	37%
Urogenital anomalies	27%	Enlarged phallus/clitoris (20%) Cryptorchidism (13%)
Cardiac anomalies	20%	ASD, VSD, PDA
Kidney anomalies	12%	Polycystic kidney, horseshoe kidney

: ASD = atrial septal defect; PDA = persistent ductus arteriosus; VSD = ventricular septal defect

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 anteroposterior axis involvement in which the frequency and degree of involvement of long bones is, in decreasing order:

Upper limbs: radii, ulnae, and humeri;
Lower limbs: fibulae, tibiae, and femurs.

The degree of limb abnormality follows a cephalocaudal pattern: the upper limbs are more severely affected than the lower, with several individuals with 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 the hands; humeral radial synostosis is also reported.

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

Mildly affected individuals have no palate 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.

Eye abnormalities include microphthalmia, nystagmus, and glaucoma. Corneal opacities can occur with occasional involvement of the crystalline lens [Ismail et al 2016].

Developmental delay and intellectual disability are common findings, segregate by family, and probably correlate 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. Individuals with intellectual disability and corneal opacities have an increased risk of intracranial aneurysms. Normal intellectual and social development have also been reported in some individuals [Petrinelli et al 1984, Stanley et al 1988, Maserati et al 1991, Holden et al 1992].

Abnormal genitalia. In affected males, enlarged penis, relatively large appearance in relation to the reduced limbs, cryptorchidism, and hypospadias are reported [Satar et al 1994]. Affected females can have an enlarged clitoris.

Heart defects. Atrial septal defect, ventricular septal defect, and patent ductus arteriosus have been reported.

Kidney manifestations. Polycystic kidney (2%), horseshoe kidney, and hydronephrosis (2%) have been reported.

Hair. Sparse hair or silvery blonde scalp hair can be seen.

Increased risk of infections and increased mortality in severely affected children due to sepsis have been reported. The increased risk of infection can continue beyond the neonatal period into late infancy.

Other

Moyamoya disease (2%) and stroke secondary to intracranial aneurysms (4%) can occur during late adolescence and young adulthood [Herrmann et al 1969, Vega et al 2010, Wang et al 2011].
Tumors/malignancy. Two individuals have had third cranial nerve paralysis related to cavernous angioma [Ogilvy et al 1993]; additional extracranial neoplasms have been reported (1 individual with malignant melanoma; 1 with rhabdomyosarcoma) [Parry et al 1986, Wenger et al 1988, Feingold 1992].

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 severely affected infants. 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 pathogenic variants with specific phenotypic features has not been established.

Nomenclature

The term SC syndrome is based on the initials of the surnames of the two families described by Herrmann et al [1969].

Other terms used for Roberts syndrome in the past include 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 173 individuals of diverse racial and ethnic backgrounds have been reported.

Recurrent variants, including c.1131+1G>A and c.760dupA, have been identified in multiple unrelated individuals. In addition, founder variants c.505C>T and c.751dupG have been reported in individuals of Colombian ancestry, and the recurrent variant c.879_880delAG has been reported in individuals of Turkish and Pakistani ancestry. Pathogenic variant c.1132-7A>G has been identified in four unrelated individuals, always in compound heterozygous form (see Table 7).

Parental consanguinity is common.

"VSports app下载" Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview have been associated with germline pathogenic variants in ESCO2.

Differential Diagnosis

While some syndromes share some of the clinical features of ESCO2 spectrum disorder, a physical examination and skeletal survey should allow for differentiation between individuals with ESCO2 spectrum disorder and those with genetic (see Table 3) or acquired conditions that are clinically similar.

Table 3.

Genes of Interest in the Differential Diagnosis of ESCO2 Spectrum Disorder

Gene(s)	Disorder	MOI	Limb Malformations	Other Clinical Features	Comment
BRCA1 BRCA2 BRIP1 ERCC4 FAAP100 FANCA FANCB FANCC FANCD2 FANCE FANCF FANCG (XRCC9) FANCI FANCL FANCM PALB2 RAD51 RAD51C REV7 (MAD2L2) RFWD3 SLX4 UBE2T XRCC2	Fanconi anemia	AR AD XL ¹	Unilateral or bilateral malformations of upper limbs (e.g., hypoplastic thumb & hypoplastic radius) & lower limbs	Bone marrow failure, ↑ risk for malignancy Physical abnormalities (e.g., short stature, abnormal skin pigmentation, microcephaly, & ophthalmic & genitourinary tract anomalies)	Disorder w/preaxial reduction defects to consider in persons w/mild manifestations
BRD4 HDAC8 NIPBL RAD21 SMC1A SMC3	"VSports app下载" Cornelia de Lange syndrome (CdLS)	AD XL ²	Upper-limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly	Distinctive craniofacial features, ³ growth restriction (prenatal onset, <5th centile throughout life), hirsutism, cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, & cryptorchidism or hypoplastic genitalia	Cytogenetic findings: PCS/HR in ESCO2 spectrum disorder is different from PSCS in CdLS, in which separation & splaying involves not only centromeric regions but also entire sister chromatids. ⁴
BUB1B CENATAC CEP57 MAD1L1 TRIP13	Mosaic variegated aneuploidy syndrome (OMIM PS257300)	AR		Severe microcephaly, growth restriction, ID Childhood cancer predisposition	Constitutional mosaicism for chromosome gains & losses Cytogenetic findings: PCS/HR in ESCO2 spectrum disorder is different from PCD in mosaic variegated aneuploidy syndrome, in which separation & splaying involves not only centromeric regions but also entire sister chromatids. ⁵
RBM8A (null allele w/RBM8A hypomorphic allele on 2 chromosomes)	Thrombocytopenia-absent radius (TAR) syndrome	AR	Bilateral absence of radii w/presence of both thumbs, plus other upper- & lower-limb skeletal anomalies	Generally transient thrombocytopenia (<50 platelets/nL) Anomalies of vertebrae, heart, & genitourinary system	Disorder to consider in persons w/severe manifestations Cleft lip & palate assoc w/skeletal changes such as absent radius suggests ESCO2 spectrum disorder rather than TAR syndrome.
RECQL4	Baller-Gerold syndrome ⁶	AR	Radial ray defect manifesting as oligodactyly; aplasia or hypoplasia of thumb &/or of radius Patellar hypo- or aplasia becomes apparent in childhood.	Coronal craniosynostosis (brachycephaly) w/ocular proptosis & prominent forehead, growth restriction, & poikiloderma	Disorder w/preaxial reduction defects to consider in persons w/mild manifestations
RSPO2 WNT3	Tetra-amelia syndrome (OMIM PS273395)	AR	Complete absence of all 4 limbs	Anomalies of cranium, face, eyes, urogenital system, anus, heart, lungs, skeleton, & CNS plus other findings	Disorder to consider in persons w/severe manifestations
SGOL1	Chronic atrial & intestinal dysrhythmia ⁷	AR		Sick sinus syndrome & chronic intestinal pseudo-obstruction co-occur during 1st 4 decades of life.	Cytogenetic testing shows evidence of PCS. Chromosomes do not display “railroad track” appearance seen in ESCO2 spectrum disorder. ⁷
TBX5	Holt-Oram syndrome (HOS)	AD	Upper-extremity malformations involving radial, thenar, or carpal bones; occasionally, phocomelia	Congenital heart malformation &/or cardiac conduction disease	Disorder to consider in persons w/severe manifestations HOS can be excluded in persons w/congenital malformations of ulnar ray only, kidney, vertebra, craniofacies, auditory system (hearing loss or ear malformations), lower limb, anus, or eye.

: AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; ID = intellectual disability; MOI = mode of inheritance; PCD = premature centromere division; PCS/HR = premature centromere separation / heterochromatin repulsion; PSCS = premature sister chromatid separation; XL = X-linked
1.: Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).
2.: NIPBL-, RAD21-, SMC3-, and BRD4-related Cornelia de Lange syndrome (CdLS) are inherited in an autosomal dominant manner; HDAC8- and SMC1A-related CdLS are inherited in an X-linked manner.
3.: Craniofacial features include synophrys, arched eyebrows, long eyelashes, small nose with anteverted nares, small, widely spaced teeth, and microcephaly.
4.: Kaur et al [2005]
5.: Plaja et al [2001]
6.: Phenotypic overlap of Baller-Gerold syndrome and Roberts syndrome was noted in an individual with bicoronal synostosis and bilateral radial hypoplasia, initially diagnosed with Baller-Gerold syndrome and later found to have premature centromere separation [Huson et al 1990].
7.: Chetaille et al [2014]

Other disorders to consider in the differential diagnosis of individuals with severe manifestations

Splenogonadal fusion with limb defects and micrognathia, characterized by abnormal fusion between the spleen and the gonad or the remnants of the mesonephros. Tetra-amelia and mild mandibular and oral abnormalities (micrognathia; multiple unerupted teeth; crowding of the upper incisors; and deep, narrow, V-shaped palate without cleft) have also been observed. The molecular basis of this phenotype (V体育ios版) has not been confirmed (OMIM 183300).
DK phocomelia syndrome, characterized by phocomelia, thrombocytopenia, encephalocele, and urogenital abnormalities. Additional malformations include cleft palate, absence of radius and digits, anal atresia, abnormal lobation of the lungs, and diaphragmatic agenesis. The molecular basis of this phenotype has not been confirmed (OMIM 223340).
Thalidomide embryopathy, characterized by 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 those with severe disease, the radius, ulna, and humerus are lacking, and the hand bud arises from the shoulders. Legs may be affected but less severely. The second major group of defects involves the ears (anotia, microtia, accessory auricles) and the eyes (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 ["VSports app下载" Franks et al 2004].
To reduce the risk of fetal exposure, the marketing and use of thalidomide in the United States is restricted through the mandatory System for Thalidomide Education and Prescribing Safety program [Zeldis et al 1999]. As of January 2005, more than 100,000 individuals have been prescribed thalidomide without any instances of drug-related birth defects [Uhl et al 2006].

Management

No clinical practice guidelines for ESCO2 spectrum disorder have been published. In the absence of published guidelines, the following recommendations are based on the literature, the experience of clinical geneticists, and authors' personal experience managing individuals with this disorder.

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.

Table 4.

ESCO2 Spectrum Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Growth restriction	Measure height, weight, & head circumference.	Assess for evidence of poor weight gain & growth deficiency.
Limb malformations	Multidisciplinary clinic assessment by orthopedist, physical medicine specialist, OT, & PT	Assess: Gross motor & fine motor skills, contractures; Need for adaptive devices to improve fine motor & gross motor skills; Possible need for surgery to improve prehensile hand grasp &/or prostheses.
Cleft lip/palate	Multidisciplinary craniofacial team assessment	Assess: Effect of lip & palatal anomalies on feeding & speech development; Need for surgical interventions.
Eye abnormalities	Assessment by pediatric ophthalmologist	Newborn: corneal opacities Adolescence & early adulthood: cranial nerve III cavernous angioma
Developmental delay / Intellectual disability	Developmental assessment	To incl: Motor, speech-language eval, & general cognitive skills Eval for early intervention / special education
Genital abnormalities	Assessment by pediatrician	Referral to pediatric urologist for further eval of cryptorchidism & hypospadias
Heart defects	Assessment by pediatric cardiologist for structural heart defects	To assess for atrial & ventricular septal defects, PDA
Kidney anomalies	Ultrasound exam	To assess for polycystic or horseshoe kidney
Infection susceptibility	Assessment by pediatric immunologist, incl serum Ig levels
Intracranial aneurysms	Assessment by neurologist incl brain imaging for vascular malformations & moyamoya disease
Malignancy	Full skin exam by dermatologist for risk of melanoma Physical exam incl assessment of cranial nerves & musculoskeletal system for masses/pain & for other signs/symptoms of malignancy
Genetic counseling	By genetics professionals ¹	To obtain a pedigree & inform affected persons & families re nature, MOI, & implications of ESCO2 spectrum disorder to facilitate medical & personal decision making
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: DD = developmental delay; ID = intellectual disability; Ig = immunoglobulin; MOI = VSports注册入口 - mode of inheritance; OT = occupational therapist; PDA = patent ductus arteriosus; PT = physical therapist
1.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Treatment is based on the affected individual's specific needs and may include the issues in Table 5.

Table 5.

ESCO2 Spectrum Disorder: Treatment of Manifestations

Manifestation/ Concern	Treatment	Considerations/Other
Poor weight gain	Assessment of caloric intake High-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
Limb malformations	Mgmt through multidisciplinary neuromuscular clinic, incl orthopedist, physical medicine specialist, & PT/OT	Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices; prostheses as indicated.
Limb malformations		Consider PT to improve range of motion & stretching, night splints, serial casts, surgery. Avoid periods of prolonged immobilization (e.g., following surgery).
Hand malformations	Hand surgery as needed for early & proper development of prehensile grasp	Hand surgeries facilitate early development of prehensile grasp & contribute to improvements in motor function.
Cleft lip & palate	Specialized cleft bottles Timing & type of surgical repair is determined by craniofacial team. The earliest surgeries are surgical cleft lip/palate repairs, which are initially performed at age 10 wks; cleft palate is usually repaired at age 6-12 mos. The optimal age range for surgery for cleft palate is 18-24 mos. Postoperative speech therapy is highly recommended.	Affected persons usually present w/fragile health that is occasionally accompanied by cardiac & kidney dysfunction; every anesthesia exposure & surgery may be life threatening. If micrognathia is also present, may be evaluated for Pierre Robin sequence.
Other craniofacial manifestations	Surgical repair for craniosynostosis & micrognathia
Eye abnormalities	Treatment per ophthalmologist for strabismus, corneal opacities, cataracts
Developmental delay / Intellectual disability	See Developmental Delay / Intellectual Disability Management Issues
Speech issues	Assessment by SLP as part of multidisciplinary craniofacial team	Interventions depend on etiology of speech issues & may incl speech therapy, surgery, &/or use of assistive communication devices.
Urogenital/kidney abnormalities	Per treating nephrologist/urologist
Congenital heart defects	Per treating cardiologist
↑ risk of infection	Prompt treatment of infections incl consultation w/infectious disease specialist as needed	Severely affected persons have ↑ mortality due to infection, & ↑ risk of infection can continue into late infancy.
Stroke	Per treating neurologist
Malignancy	Treatment per oncologist
Family/Community	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.	Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics.

: DD = developmental delay; ID = intellectual disability; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

ESCO2 Spectrum Disorder: Recommended Surveillance

System/Concern	Evaluation	Frequency
Growth	Assess growth incl weight, height, & head circumference.	At every visit
Limb malformations	Assessment of mobility, self-help skills, & need for architectural modifications at home by physical medicine specialist & OT/PT	At every visit
Cleft lip/palate	Multidisciplinary craniofacial team: Assess equipment & techniques for feeding infants w/cleft palate. Determine surgical repair timing & type of procedure. Audiologic eval as needed	In infants: visit frequency determined by feeding & respiratory issues In children: varies depending on comorbidities; at least annually
Development	Monitor developmental progress & educational needs, mobility, & self-care needs. Assess for household barriers to mobility/self-help.	At every visit
Speech	Speech assessment by SLP familiar w/cleft palate & neuromuscular contributors to speech issues Consider speech therapy, surgical interventions, & augmentative communication devices.	At least annually
Kidney anomalies	Blood pressure measurement	At each visit
Kidney anomalies	Kidney function tests	Annually
Eye abnormalities	Visual acuity	Per treating ophthalmologist
Congenital heart defects	Per treating cardiologist / cardiac surgeon	Per treating cardiologist / cardiac surgeon
Malignancies	Physical exam incl full skin exam & neurologic exam for evidence of malignancy	Annually
Stroke	Referral to neurologist incl brain imaging for vascular anomalies & aneurysms	In those w/ID, corneal opacities, &/or heart defects
Stroke	Assess for clinical manifestations of aneurysms & vascular malformations.	Annually starting in adolescence
Infection risk	Assess frequency of infections.	At each visit
Infection risk	Ig serum level	During infancy
Family/ Community	Assess need for architectural adaptations at home based on level of physical & intellectual disability.	According to developmental & physical needs

: ID = intellectual disability; Ig = immunoglobulin; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

V体育官网入口 - Mode of Inheritance

ESCO2 spectrum disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are presumed to be heterozygous for an ESCO2 pathogenic variant.
Molecular genetic testing is recommended for the parents of a "V体育ios版" proband to confirm that both parents are heterozygous for an ESCO2 pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a V体育平台登录 - proband

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 being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

Pregnancies in individuals with an ESCO2 spectrum disorder are rare; two have been reported, one resulting in an unaffected girl and the other resulting in a second-trimester miscarriage [Parry et al 1986].
The offspring of an individual with an ESCO2 spectrum disorder are obligate heterozygotes (carriers) for a "VSports手机版" pathogenic variant in ESCO2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ESCO2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ESCO2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer VSports最新版本 - genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for an ESCO2 pathogenic variant, particularly if consanguinity is likely and/or if both partners are of the same ancestry (see Prevalence). An ESCO2 founder variant has been identified in individuals of Colombian ancestry (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

VSports最新版本 - Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancy

Molecular genetic testing. Once the ESCO2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Ultrasound examination combined with cytogenetic testing. Prenatal testing for pregnancies at increased risk is possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling. These findings in conjunction with ultrasound examination to follow growth and to evaluate the limbs, heart, palate, and other organs or structures affected in ESCO2 spectrum disorder can be used for prenatal diagnosis of the syndrome [Kennelly & Moran 2007].
Note: The sensitivity of prenatal ultrasound examination for ESCO2 spectrum disorder is 41%-65% [Mengen et al 2018].

Low-risk pregnancy. The diagnosis of ESCO2 spectrum disorder can be established in a fetus with suggestive findings on prenatal ultrasound (growth restriction, limb malformations, craniofacial and other reported anomalies) by identification of either biallelic ESCO2 pathogenic variants by molecular genetic testing or premature centromere separation by cytogenetic testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

V体育官网入口 - Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Children's Craniofacial Association
Phone: 800-535-3643
Email: contactCCA@qiuluzeuv.cn
ccakids.org
Face Equality International
United Kingdom
faceequalityinternational.org
REACH
Helping children with upper limb differences live life without limits.
United Kingdom
Phone: 03003650078
Email: reach@qiuluzeuv.cn
reach.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ESCO2 Spectrum Disorder: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
ESCO2	8p21.1	N-acetyltransferase ESCO2	Establishment of Cohesion 1 homolog 2 (ESCO2) @ LOVD	ESCO2	ESCO2

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ESCO2 Spectrum Disorder (View All in OMIM)

268300	ROBERTS-SC PHOCOMELIA SYNDROME; RBS
609353	ESTABLISHMENT OF SISTER CHROMATID COHESION N-ACETYLTRANSFERASE 2; ESCO2

Molecular Pathogenesis (V体育2025版)

ESCO2 encodes N-acetyltransferase ESCO2 (ESCO2), an acetyltransferase [Gordillo et al 2008] associated with two different complexes: MCM helicase [Ivanov et al 2018] and PCNA [Bender et al 2020]. ESCO2 travels with the MCM and PCNA complexes during DNA replication and acetylates the cohesion complex, a ring-shaped complex involved in sister chromatid cohesion and control of gene transcription. ESCO2 acetylates the cohesin complex subunit SMC3 at lysine residues, contributing to the stability of the binding of the cohesion complex with the DNA, holding together just-replicated sister chromatids [Yatskevich et al 2019].

Without ESCO2, metaphase chromosomes lack primary constrictions and show impaired centromeric cohesion; however, the sister chromatids are held together by arm cohesion, allowing their metaphase alignment. Cells proceed to anaphase despite the lack of centromeric cohesion [Vega et al 2005]. Cell division is highly inefficient with low cell viability, high frequency of aneuploidy with micronucleation, and increased apoptosis of progenitor cells [Gordillo et al 2008, Mönnich et al 2011].

There is evidence that cohesin binding contributes to the formation of DNA loops, allowing the physical association of distant promoters or enhancers that affect gene transcription. Although cells in ESCO2 spectrum disorder have an abnormal gene expression profile [Liu et al 2009, Xu et al 2013, Banerji et al 2016], the clinical significance of disruption of gene expression is unknown.

To date, 35 different ESCO2 pathogenic variants have been described in affected individuals. Most are indel pathogenic variants that result in premature stop codons. Missense pathogenic variants are rarely identified [Vega et al 2005, Vega et al 2010]. Large ESCO2 rearrangements have not been described.

Mechanism of disease causation. Loss of function

Table 7.

ESCO2 Pathogenic Variants Referenced in This GeneReview

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_001017420.3 NP_001017420.1	c.505C>T	p.Arg169Ter	Founder variants in Colombia [Vega et al 2005]
	c.751dupG	p.Glu251GlyfsTer30	Founder variants in Colombia [Vega et al 2005]
	c.760dupA	p.Thr254AsnfsTer27	Recurrent variant found in 4 unrelated families [Schüle et al 2005, Gordillo et al 2008, Afifi et al 2016, McKay et al 2019]
	c.879_880delAG	p.Arg293SerfsTer7	Recurrent variant in persons of Turkish [Vega et al 2005] & Pakistani ancestry [Schulz et al 2008]; also reported in other unrelated persons [Gordillo et al 2008, Gerkes et al 2010]
NM_001017420.3	c.1131+1G>A	--	Recurrent variant found in multiple unrelated persons [Schüle et al 2005, Vega et al 2010, Dogan et al 2014, Dupont et al 2014, Colombo et al 2019]
NM_001017420.3	c.1132-7A>G	--	Recurrent variant found in 4 compound heterozygous persons [Schüle et al 2005, Gordillo et al 2008, Vega et al 2010, McKay et al 2019]

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Hugo Vega (moc.liamg@agevuh) is actively involved in clinical research regarding individuals with ESCO2 spectrum disorder. Dr Vega would be happy to communicate with persons who have any questions regarding diagnosis of Roberts syndrome, SC phocomelia syndrome, or other considerations.

Revision History

14 August 2025 (sw) Comprehensive update posted live
26 March 2020 (bp) Comprehensive update posted live
14 November 2013 (me) Comprehensive update posted live
2 October 2008 (me) Comprehensive update posted live
18 April 2006 (me) Review posted live
2 December 2005 (ewj) Original submission

VSports app下载 - References

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Vega H, Gordillo M, Jabs EW. ESCO2 Spectrum Disorder. 2006 Apr 18 [Updated 2025 Aug 14]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
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