ESCO2 Spectrum Disorder

Disease Overview

Summary

ESCO2 spectrum disorder includes conditions caused by changes (variants or mutations) in the ESCO2 gene that range from Roberts syndrome at the severe end to SC phocomelia at the milder end. Roberts syndrome is the best known and most widely studied condition in this group. These conditions are inherited in an autosomal recessive pattern.

Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth, malformations of the arms and legs, and distinctive abnormalities of the skull and facial (craniofacial) region. Intellectual disability occurs in about half of affected children. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities), however, such limb defects are usually symmetrical which are distinct from the asymmetrical limb defects in Cornelia de Lange syndrome (CdLS). Such abnormalities may range from absence of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of certain bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or on the outside of the lower legs (fibulae). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); abnormal grooves on either side of the upper lip (bilateral cleft lip); incomplete development of the roof of the mouth (cleft palate); thin, small wings of the nose (hypoplastic nasal alae) and/or low-set, malformed (dysplastic) ears. Additional abnormalities are often present.

Introduction

Initially, researchers believed that Roberts syndrome and SC phocomelia syndrome were separate disorders. However, researchers now believe that the two disorders are different expressions of one distinct disorder because different changes in the same gene are the underlying cause for both conditions. Juberg-Hayward syndrome is a malformation syndrome characterized by cleft lip/palate, microcephaly, drooping upper eye lids (ptosis), short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction.

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Subdivisions

• Roberts syndrome
• SC phocomelia
• Juberg-Hayward syndrome

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Signs & Symptoms

The symptoms associated with Roberts syndrome vary widely from person to person even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.

Affected infants may experience growth deficiencies before and after birth. Intellectual disability is a variable finding that occurs in approximately 50 percent of affected children.

Limb abnormalities are common in infants with Roberts syndrome and may range from underdeveloped bones in the arms and legs (hypomelia) to complete absence of all four limbs (tetraphocomelia). The arms are usually more severely affected than the legs.

Additional abnormalities may affect the arms and legs including permanent fixation (contracture) of various joints, especially the knees and elbows. The number of fingers and/or toes may be reduced, and the fifth fingers may be in a fixed laterally deviated position (clinodactyly). Webbing of the finger and toes (syndactyly) may also be present. Infants with Roberts syndrome may also have a form of club foot where the heel of the foot may be elevated and turned outward away from the body (talipes equinovalgus).

Infants with Roberts syndrome also have a variety of craniofacial abnormalities including a small, broad head (microbrachycephaly); an abnormal groove in the upper lip (cleft lip) with or without incomplete closure of the roof of the mouth (cleft palate); a flattened nose with small wings; an abnormally small jaw (micrognathia); sparse, silvery hair; and malformed, low-set ears that often lack lobes. Some infants may experience premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). Affected infants may have eye (ocular) abnormalities including widely spaced eyes (hypertelorism); unusually small eyes (microphthalmia); cloudy corneas; and bulging or prominent eyes (proptosis) due to shallow eye cavities (orbits). In some children, the whites of the eyes may be blue (blue sclera) and increased pressure within the eyeball (glaucoma) may also be present.

Some infants with Roberts syndrome may have one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries).

Infants with Roberts syndrome often have abnormalities affecting the genitourinary system. Males may have the urinary opening located on the underside of the penis (hypospadias) and the testicles may fail to descend into the scrotum (cryptorchidism). Females may have a malformed uterus with horn-like branches (bicornuate uterus).

Less common symptoms associated with Roberts syndrome include malformed kidneys, an abnormal increase in cerebrospinal fluid resulting in enlargement of the skull (hydrocephalus), paralysis of cranial nerves, seizures, heart defects and a decreased number of blood platelets (thrombocytopenia).

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Causes

The ESCO2 spectrum disorders, including Roberts syndrome, are caused by changes (variants or mutations) in the ESCO2 gene.

Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. There are certain complex chromosomal abnormalities which are distinguishing features of ESCO2 spectrum disorders. Cells from affected individuals show premature centromere separation of various chromosomes, especially chromosomes 1, 9, and 16, a phenomenon often referred to as “puffing.” The centromere is the center of a chromosome located between the long and short arms of a chromosome. The characteristic “puffing” abnormality is apparent in mitosis, the process in which a cell divides ultimately forming two cells identical to the original.

ESCO2 spectrum disorders, including Roberts syndrome, are inherited in an autosomal recessive pattern. Genetic diseases of this type are determined by two abnormal genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

It is also possible that a new mutation in an autosomal dominant gene could be the cause of Roberts syndrome in some families. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

ESCO2 spectrum disorders affect males and females in equal numbers. Affected children often have parents who are blood relatives. Patients have been reported from all over the world. The two families with Juberg-Hayward syndrome were identified in a tribe in Thailand with the identical ESCO gene mutation.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:

Cornelia de Lange syndrome (CdLS) is a dominantly inherited, multi-system developmental disorder. The asymmetrical upper limb defects are similar but different from those in Roberts syndrome, which is ranging from small hands with single palmar creases and subtle changes in the bones of fingers (phalanges) and the palm (metacarpal bones) to severe forms of lack of fingers (oligodactyly) and truncation of the forearm primarily involving the structures on “pinky” side (ulnar). The characteristic facial features seen in individuals with CdLS are easy to identify and may be one of the most useful diagnostic signs, which includes one fused heavy eyebrow (synophrys), long eyelashes, depressed nasal bridge, long philtrum, thin upper lip, small widely spaced teeth, disproportionate small and short head (brachycephaly), and low-set ears. Other common clinical presentations are excessive bodily or facial hair (hirsutism), various eye (ophthalmologic) problems, stomach and esophagus (gastroesophageal) dysfunction, heart defects, growth delay, and neurodevelopmental delay. The intellectual disability seen in CdLS is severe; autism and self-destructive tendencies are also seen in many patients. Mildly affected patients may go undiagnosed.About 50% of CdLS patients have a mutation in the NIPBL gene and a small portion of patients have mutations in the SMC1A or SMC3 gene, while the rest have no reported gene mutations. SMC1A and SMC3 proteins are structural subunits of the cohesin complex. Both ESCO2 (the disease-causing gene of RBS) and NIPBL regulate cohesin complex, although through different mechanisms. (For more information on this disorder, choose “CdLS” as your search term in the Rare Disease Database.)

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhages) primarily during infancy. Other characteristic findings include absence (aplasia) of the bones on the thumb side of the forearms (radii) and underdevelopment (hypoplasia) or absence of the bones on the “pinky” side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or intellectual disability that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “TAR syndrome” as your search term in the Rare Disease Database.)

Baller-Gerold syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In infants with Baller-Gerold syndrome, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular (trigonocephaly). Affected infants may also have a prominent forehead; down slanting eyelid folds (palpebral fissures); small, malformed (dysplastic), low-set ears; and/or other craniofacial abnormalities. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii). In addition, the bone on the “pinky” side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. In some patients, additional physical abnormalities and/or intellectual disability may also be present. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern and caused by mutations in the RECQL4 gene (For more information on this disorder, choose “Baller Gerold” as your search term in the Rare Disease Database.)

Holt-Oram syndrome (HOS), also known as cardiac-limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic) or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper and/or lower chambers of the heart (atrial and/or ventricular septal defects), or abnormal transmission of electrical impulses that coordinate the heart’s muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited in an autosomal dominant pattern or appear to occur spontaneously due to new genetic mutations. Mutations in the TBX5 gene have been associated with HOS (For further information, choose “Holt Oram” as your search term in the Rare Disease Database.)

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Diagnosis

A diagnosis of ESCO2 spectrum disorders, including Roberts syndrome, is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be supported by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. The diagnosis is confirmed by molecular testing for ESCO2 gene mutations. The presence of mutations in this gene is strictly correlated with the centromere puffing phenomenon.

In some children, it is possible that a diagnosis of ESCO spectrum disorder may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis, chorionic villus sampling (CVS) or ultrasonography. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In families with high risk where both parents are carriers, DNA sequencing of fetal samples can detect an ESCO2 mutation. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive of the diagnosis (e.g., cleft lip/palate, limb abnormalities).

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Standard Therapies

Treatment
The treatment of ESCO spectrum disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, neurologists, eye specialists, and other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.

Patients may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Gordillo M, Vega H, Jabs EW. ESCO2 and Roberts syndrome. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed, Chap 111. New York: Oxford University Press; 2008:1011-9.

Mandal AK. Roberts Pseudothalidomide Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:244-5.

Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990.

Jones KL., ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:298.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:735-8.

JOURNAL ARTICLES
Kantaputra PN, Dejkhamron P, Intachai W, Ngamphiw C, Kawasaki K, Ohazama A, Krisanaprakornkit S, Olsen B, Tongsima S, Ketudat Cairns JR. Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2. Eur J Orthod. 2021 Jan 29;43(1):45-50. doi: 10.1093/ejo/cjaa023. PMID: 32255174.

Kantaputra PN, Dejkhamron P, Tongsima S, Ngamphiw C, Intachai W, Ngiwsara L, Sawangareetrakul P, Svasti J, Olsen B, Cairns JRK, Bumroongkit K. Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2. Arch Oral Biol. 2020 Nov;119:104918. doi: 10.1016/j.archoralbio.2020.104918. Epub 2020 Sep 16. PMID: 32977150.

Vega H, Trainer AH, Gordillo M, et al. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J Med Genet. 2010;1:30-7.

Schule B, Oviedo A, Johnston K, Pai S, Francke U. Inactivating mutations in ESCO2 cause SC Phocomelia and Roberts syndrome: no phenotype-genotype correlation. Am J Med Genet. 2005;117-28.

Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, Jukofsky L, Wasserman N, Bottani A, Morris CA, Nowaczyk MJ, Toriello H, Bamshad MJ, Carey JC, Rappaport E, Kawauchi S, Lander AD, Calof AL, Li HH, Devoto M, Jackson LG. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet. 2004 Jun;36(6):631-5.

Hwang K, et al. Roberts syndrome, normal cell division, and normal intelligence. J Craniofacial Surg. 2002;13:390-4.

Maheshwari A, et al. Roberts-SC phocomelia syndrome. Indian J Pediatr. 2001;68:557-9.

McDaniel LD, et al. Novel assay for Roberts syndrome assigns variable phenotypes to one complementation group. Am J Med Genet. 2000;93:223-9.

Camlibel T, et al. Roberts SC phocomelia with isolated cleft palate, thrombocytopenia, and eosinophilia. Genet Couns. 1999;10:157-61.

Petrikovsky BM, et al. Prenatal diagnosis of pseudothalidomide syndrome in consecutive pregnancies of a consanguineous couple. Ultrasound Obstet Gynecol. 1997;10:425-8.

Concolino D, et al. A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of upper limbs. Clin Genet. 1996;49:274-6.

Van den Berg DJ, Francke U. Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet. 1993;15:1104-23.

Van den Berg DJ, Francke U. Sensitivity of Roberts syndrome cells to gamma radiation, mitomycin C, and protein synthesis inhibitors. Somat Cell Mol Genet. 1993;19:377-92.

Holden KR, Jabs EW, Sponseller PD. Roberts/pseudothalidomide syndrome and normal intelligence: approaches to diagnosis and management. Dev Med Child Neurol. 1992;34:534-9.

Sherer DM, et al. Prenatal sonographic features and management of a fetus with Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) and pulmonary hypoplasia. Am J Perinatol. 1991;8:259-62.

Keppen LD, et al. Roberts syndrome with normal cell division. Am J Med Genet. 1991;38:21-4.

Romke C, et al. Roberts syndrome and SC phocomelia. A single genetic entity. Clin Genet. 1987;31:170-7.

INTERNET
Vega H, Gordillo M, Jabs EW. ESCO2 Spectrum Disorder. 2006 Apr 18 [Updated 2020 Mar 26]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1153/ Accessed May 11, 2023.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:268300; Last Update: 01/03/2023. Available at https://omim.org/entry/268300 Accessed May 11, 2023.

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