Roberts syndrome

Roberts syndrome also known as SC phocomelia syndrome, RBS, Appelt-Gerken-Lenz syndrome, hypomelia hypotrichosis facial hemangioma syndrome, Roberts-SC phocomelia syndrome, tetraphocomelia-cleft palate syndrome or pseudothalidomide syndrome, is an extremely rare genetic autosomal recessive disease characterized by craniofacial deformities, limb abnormalities and intellectual disability ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. Affected individuals are born with abnormalities of all four limbs and typically have shortened arm and leg bones (hypomelia). They may also have phocomelia (a birth defect in which infants born with phocomelia will have arms and/or legs that are severely shortened or sometimes completely absent); abnormal or missing fingers and toes; joint deformities (contractures); and numerous facial abnormalities including cleft lip with or without opening in the roof of the mouth (cleft palate); micrognathia; ear abnormalities; wide-set eyes (hypertelorism); down-slanting palpebral fissures; small nostrils; and a beaked nose. Microcephaly (baby’s head is significantly smaller than expected), intellectual disability, and heart, kidney or genital abnormalities may also be present. The limb defects are similar to those seen in thalidomide embryopathy; hence, Roberts syndrome is also known as pseudothalidomide syndrome ².

This disease was first described in 1919 by John Roberts who 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 ¹⁸. But earlier reports of tetra phocomelia and facial anomalies are cited since 1670s ¹⁰.

Roberts syndrome was previously referred as “pseudothalidomide syndrome”, based on the similarities regarding limb malformations with thalidomide syndrome patients ¹⁹. In 1969, J Herrmann and colleagues ²⁰ 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’. SC phocomelia syndrome was originally thought to be distinct from Roberts syndrome; however, it is now considered to be a mild variant of Roberts syndrome ²⁰. “SC” represents the first letters of the surnames of the two families first diagnosed with this disorder ²⁰.

Roberts syndrome is an extremely rare condition with only about 150 cases have been described in literature ⁴, ²¹, ²², ²³, ²⁴.

Roberts syndrome is caused by mutation in the “establishment of cohesion 1 homolog 2” (ESCO2) gene on chromosome 8p21.1 (short arm of chromosome 8), resulting in the loss of acetyltransferase activities and manifesting as premature centromere separation in metaphase chromosomes ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹. The ESCO2 gene is an essential gene that targets the DNA-binding cohesin complex ³², ³³, ³⁴, ³⁵. The ESCO2 gene provides instructions for making a protein that is important for proper chromosome separation during cell division. Before cells divide, they must copy all of their chromosomes. The copied DNA from each chromosome is arranged into two identical structures, called sister chromatids. The ESCO2 protein plays an important role in establishing the glue that holds the sister chromatids together until the chromosomes are ready to separate. Aneuploidy with random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells are also characteristics of Roberts syndrome ³⁵.

Roberts syndrome occurs equally in both males and females, and is common among closely related parents (parental consanguinity) ², ²⁴.

The diagnosis of Roberts syndrome can be made clinically in individuals with characteristic intrauterine growth restriction, limb malformation, and craniofacial abnormalities ¹¹, ³⁶. However, the gold standard for diagnosis is cytogenetic testing ³⁷. A high index of suspicion is needed as Roberts syndrome is extremely rare. Regular antenatal ultrasounds play a significant role in preventing Roberts syndrome, especially in consanguineous couples. An experienced sonographer can suspect Roberts syndrome with prenatal ultrasound where structural defects can be well defined ¹¹, ³⁶, ³⁸, ³⁹. Postnatal cytogenetic testing of the biopsied tissue confirms the diagnosis ², ⁴⁰. In low-income countries, clinical diagnosis can be made where genetic diagnosis is not feasible ².

Mildly affected individuals can survive to adulthood, but infants with a severe form of Roberts syndrome result in spontaneous abortion, stillbirth, or die shortly after birth within 1 month ⁴¹, ⁴², ⁶. The treatment of Roberts syndrome is limited to prevention, surgery to correct physical malformations, prostheses, special education, speech therapy, and treatments for organ dysfunction ⁴², ⁶.

Figure 1. Roberts syndrome

Footnotes: Photographs of patients with Roberts syndrome (RBS). (A,B) Patient with the ESCO2 c.505C>T mutation in the neonatal period (A) and 1 year later (B). (C,D,E) Patient with ESCO2 c.879_880delAG mutation. (A,C) Roberts syndrome facies with microcephaly, hypoplastic nasal alae, malar hypoplasia, hypertelorism, micrognathia, hemangioma, exophthalmos, down-slanting palpebral fissures and cleft lip and palate. (B,D,E) Roberts syndrome limb reduction is mesomelic, symmetric and follows a cephalocaudal pattern in which the arms are more severely affected than the legs.

[Source ⁴³ ]

Roberts syndrome causes

Roberts syndrome is caused by mutation in the “establishment of cohesion 1 homolog 2” (ESCO2) gene on chromosome 8p21.1 (short arm of chromosome 8), resulting in the loss of acetyltransferase activities and manifesting as premature centromere separation in metaphase chromosomes ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹. The ESCO2 gene is an essential gene that targets the DNA-binding cohesin complex ³², ³³, ³⁴, ³⁵. The ESCO2 gene provides instructions for making a protein that is important for proper chromosome separation during cell division. Before cells divide, they must copy all of their chromosomes. The copied DNA from each chromosome is arranged into two identical structures, called sister chromatids. The ESCO2 protein plays an important role in establishing the glue that holds the sister chromatids together until the chromosomes are ready to separate. Aneuploidy with random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells are also characteristics of Roberts syndrome ³⁵.

All identified mutations in the ESCO2 gene prevent the cell from producing any functional ESCO2 protein, which causes some of the glue between sister chromatids to be missing around the chromosome’s constriction point (centromere). In Roberts syndrome, cells respond to abnormal sister chromatid attachment by delaying cell division. Delayed cell division can be a signal that the cell should undergo self-destruction. The signs and symptoms of Roberts syndrome may result from the loss of cells from various tissues during early development. Because both mildly and severely affected individuals lack any functional ESCO2 protein, the underlying cause of the variation in disease severity remains unknown. Researchers suspect that other genetic and environmental factors may be involved ⁵, ³.

Preimplantation genetic testing are important in the management of Roberts syndrome ². This has become imperative because the parents of an affected child are obligate heterozygotes (i.e. presumed to be carriers of one ESCO2 pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an ESCO2 pathogenic variant and allow reliable recurrence risk assessment ².

Roberts syndrome inheritance pattern

Roberts syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Although a new (de novo) mutations has not been reported in ESCO2 spectrum disorder to date, de novo mutations are known to occur at a low but appreciable rate in autosomal recessive disorders. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Figure 2. Roberts syndrome autosomal recessive inheritance pattern

Roberts syndrome symptoms

Individuals with Roberts syndrome grow slowly before and after birth. Mild to severe intellectual impairment occurs in about half of all people with Roberts syndrome.

Children with Roberts syndrome are born with abnormalities of all four limbs. They have shortened arm and leg bones (hypomelia), particularly the bones in their forearms and lower legs. In severe cases, the limbs may be so short that the hands and feet are located very close to the body (phocomelia). People with Roberts syndrome may also have abnormal or missing fingers and toes, and joint deformities (contractures) commonly occur at the elbows and knees. The limb abnormalities are very similar on the right and left sides of the body, but arms are usually more severely affected than legs.

Individuals with Roberts syndrome typically have numerous facial abnormalities, including an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (cleft palate), a small chin (micrognathia), ear abnormalities, wide-set eyes (hypertelorism), outer corners of the eyes that point downward (down-slanting palpebral fissures), small nostrils, and a beaked nose. They may have a small head size (microcephaly) or clouding of the clear front covering of the eyes (corneal opacities). In severe cases affected individuals have a sac-like protrusion of the brain (encephalocele) at the front of their head. In addition, people with Roberts syndrome may have heart, kidney, and genital abnormalities.

Children with Roberts syndrome have sparse hair, silvery blonde scalp hair.

Occasionally, Roberts syndrome patients have third cranial nerve paralysis related to cavernous angioma ⁴⁴; additional extracranial neoplasms have been reported, 1 case with malignant melanoma, 1 with rhabdomyosarcoma ⁴⁵, ⁴⁶, ⁴⁷.

Moyamoya disease (2%) and stroke secondary to intracranial aneurysms (4%) occurred during late adolescence and young adulthood ⁴⁸, ⁴³.

Infants with a severe form of Roberts syndrome are often stillborn or die shortly after birth. Mildly affected individuals may live into adulthood.

Table 1. Roberts syndrome clinical features

Clinical Feature	Proportion of Individuals with Clinical Feature	Comment
Growth deficiency	49/49 (100%)	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.
Microcephaly	38/40 (95%)
Phocomelia	53/53 (100%)	Upper limbs only (21%) Upper & lower limbs (79%)
Bone fusions	15/23 (65%)	Knees, ankles, wrists, elbows, talipes equinovarus, syndactyly (18%) Flexion contractures (16%)
Cleft lip & palate	29/48 (56%)	Cleft palate only (5%)
Developmental delay / intellectual disability	23/38 (61%)	Intellectual disability is present in the majority of affected individuals; normal intellectual and social development have also been reported 49, 50, 51, 52
Eye abnormalities	(37%)	Corneal opacities (33%) Microphthalmia (8%) Nystagmus (8%) Glaucoma (8%)
Urogenital anomalies	14/30 (48%)	Cryptorchidism (22%) Enlarged phallus (33%) Enlarged clitoris (45%)
Kindey anomalies	1/8 (12%)	Polycystic kidney (2%), horseshoe kidney, hydronephrosis (2%)
Heart anomalies	10/34 (29%)	Atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA)

[Source ⁴⁰ ]

Roberts syndrome diagnosis

The diagnosis of Roberts syndrome can be made clinically in individuals with characteristic intrauterine growth restriction, limb malformation, and craniofacial abnormalities ¹¹, ³⁶. However, the gold standard for diagnosis is cytogenetic testing ³⁷.

Roberts syndrome should be suspected in an individual with the following clinical findings and family history.

Clinical findings ⁵³, ⁵⁴, ⁴³:

• 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.
• Urogenital abnormalities: cryptorchidism, enlarged phallus
• Kidney anomalies: horseshoe kidney, polycystic kidney
• Heart defects: ventricular septal defect
• Eye abnormalities: corneal opacities
• Sparse hair

Regular antenatal ultrasounds play a significant role in preventing Roberts syndrome, especially in consanguineous couples. An experienced sonographer can suspect Roberts syndrome with prenatal ultrasound where structural defects can be well defined ¹¹, ³⁶, ³⁸, ³⁹. Postnatal cytogenetic testing of the biopsied tissue confirms the diagnosis ², ⁴⁰. In low-income countries, clinical diagnosis can be made where genetic diagnosis is not feasible ².

Cytogenetic preparations are stained by Giemsa or C-banding techniques, which show premature centromere separation (PCS) and their centromeres separate during metaphase rather than anaphase. The second chromosomal abnormality is heterochromatin repulsion and chromosome with heterochromatin repulsion experience separation of heterochromatin regions during metaphase. Both abnormalities give the chromosome “a railroad track” appearance ²³, ³³, ³⁴, ³⁵. Other findings which may be found on the chromosome in Roberts syndrome include aneuploidy, micronucleation, and multilobulated nuclei ⁵⁵.

Family history consistent with autosomal recessive inheritance, including consanguinity (a union between two individuals who are related as second cousins or closer) ⁴⁰.

Roberts syndrome treatment

Roberts syndrome treatment is based on the affected individual’s symptoms and specific needs with the involvement of a multidisciplinary team of plastic surgeon, pediatrician, orthopedics, physiotherapist, speech therapist, cardiologist, nephrologist, eye specialist, social workers, and genetic counselors ⁴², ⁶. The aim of treatment in mild forms is to improve the quality of life of children affected with Roberts syndrome. The possible corrections include correction of cleft lip and palate, surgical correction of limb abnormalities, and management of cognitive disabilities ⁵², ⁴⁰.

Roberts syndrome is characterized by growth retardation (mild to severe), craniofacial anomalies (microcephaly, dolichocephaly, cleft palate, micrognathia, premaxillary prominence, microbrachycephaly, downslanted palpebral fissures, widely spaced eyes, exophthalmos, corneal clouding, ear malformations), limb malformations (bi-/tetra-phocomelia, hypomelia, oligodactyly with thumb aplasia, syndactyly, clinodactyly), more severe to the upper limbs ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁴⁰.

• 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 augmentative and alternative communication 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.
• Social/Behavioral Concerns. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Table 2. Roberts syndrome treatment

Symptoms / Concern	Treatment	Considerations/Other
Poor weight gain / Weight-faltering	Assessment of caloric intake; high-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
Limb malformations	Multidisciplinary neuromuscular clinic physical medicine, physical therapy or occupational therapy	Maximize gross motor & fine motor skills through physical therapy or occupational therapy & use of adaptive devices; prostheses as indicated.
	Orthopedics	Consider: physical therapy to improve range of motion; Stretching, night splints, serial casts, surgery. Avoid periods of prolonged immobilization (e.g., following surgery).
Hand malformations	Hand surgeon	Hand surgery as needed for early & proper development of prehensile grasp
Cleft palate	Specialized cleft bottles; timing & type of surgical repair determined by craniofacial team 1	If micrognathia also present, may be evaluated for Pierre Robin sequence
Developmental delay / intellectual disability	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.
Speech issues	Assessment by speech language pathologist 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 abnormalities	Per treating nephrologist/urologist
Renal anomalies
Congenital heart defects	Per treating cardiologist
Eye abnormalities	Per treating ophthalmologist
Stroke	Per treating neurologist
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.

[Source ⁴⁰ ]

Table 3. Roberts syndrome recommended surveillance

Concern	Evaluation	Frequency
Growth	Primary care provider: monitor growth incl weight, height, & head circumference, blood pressure, risk of infection.	At every visit
Development	Monitor developmental progress & educational needs, mobility & self-care needs. Assess for household barriers to mobility/self-help.	At every visit
Limb malformations	Physical medicine, occupational therapy / physical therapy assessment of mobility, self-help skills, and need for architectural modifications at home	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 evaluation as needed	In infants: visit frequency determined by feeding & respiratory issues In children: varies depending on comorbidities; at least annually
Speech	Speech assessment by speech language pathologist familiar w/cleft palate & neuromuscular contributors to speech issues Consider speech therapy, surgical interventions, & augmentative communication devices.	At least annually
Renal anomalies	Renal function test, blood pressure measurement	Annually
Congenital heart defects	Per treating cardiologist / cardiac surgeon	Per treating cardiologist / cardiac surgeon
Eye abnormalities	Visual acuity	Per treating ophthalmologist
Malignancies	Skin, musculoskeletal, & intracranial	Annually
Stroke	Aneurysms, vascular malformation, & intracranial neoplasms	Starting in adolescence
Infection risk	Ig serum level	During infancy
Family/ Community	Architectural adaptations at home based on level of physical & intellectual disability	According to developmental & physical needs

[Source ⁴⁰ ]

Roberts syndrome prognosis

Roberts syndrome prognosis depends on the severity of structural malformations and involvement of other organs ⁴⁰. Infants with a severe form of Roberts syndrome are often stillborn or die shortly after birth. Mildly affected individuals may live into adulthood ⁶¹, ⁶². Roberts-SC phocomelia represents the milder form of Roberts syndrome and typically survive to adulthood ⁶¹. The cause of death has not been reported for most affected individuals. The majority of infants with Roberts syndrome die due to heart, kidney abnormalities and neonatal infective complications ². Reported causes of death are infection (5 individuals), aneurysm/hemorrhage (3 individuals), and cancer (3 individuals) ⁸, ⁴³. Perinatal mortality is correlated with severity of the malformations; early death is usually secondary to respiratory complications and infection ¹⁰.

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