ロバーツ症候群（ESCO2関連コヒーシノパチー）【ESCO2】

2025.10.16

やさしいまとめ

Roberts syndrome is an extremely rare genetic condition that affects growth, limb development, and facial structures. This guide explains its genetic cause, clinical features, diagnostic methods, and current approaches to management, offering clear, scientifically grounded information for patients, families, and healthcare providers.

Roberts Syndrome Overview

ESCO2

Roberts syndrome, also known as ESCO2-related cohesinopathy, is a very rare genetic disorder caused by mutations in the ESCO2 gene. It primarily affects fetal growth and the proper development of limbs, facial structures, and, in some cases, internal organs. The condition is inherited in an autosomal recessive pattern, meaning both parents must carry the same genetic mutation for the child to be affected. Fewer than 150 cases have been documented worldwide, but the actual number is likely higher due to underdiagnosis and the variability of symptoms.

The ESCO2 Gene

Location and Function

The ESCO2 gene (Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2) is located on the short arm of chromosome 8, position 21.1 (GRCh38: chr8:27,771,949–27,819,660). It encodes an enzyme made of 601 amino acids that plays a critical role in cell division.

During the S phase of the cell cycle, when DNA is replicated, ESCO2 acetylates a protein called SMC3. This acetylation helps keep sister chromatids tightly connected until they are properly separated later in cell division. ESCO2 interacts closely with other cell cycle regulators such as PCNA (Proliferating Cell Nuclear Antigen) and the MCM helicase complex. Disruption of this process interferes with chromosome segregation, leading to developmental abnormalities.

Disease Characteristics

Genetic Basis

Roberts syndrome arises when mutations are present in both copies of the ESCO2 gene. As an autosomal recessive disorder, the chance of an affected child is 25% if both parents are carriers. The disease belongs to the group of disorders known as cohesinopathies, which share defects in chromosome cohesion during cell division.

Key Clinical Features

Typical findings include:

Severe growth restriction starting before birth
Symmetric limb malformations, such as shortening of arms and legs
Cleft lip and/or palate
Microcephaly (smaller-than-average head size)
Chromosomal abnormalities known as the RS effect

The RS effect refers to premature separation of centromeres or heterochromatin repulsion, observable under a microscope, and is considered a hallmark diagnostic sign.

Severity varies widely. Some individuals exhibit profound physical differences and significant medical challenges at birth, while others have milder presentations that permit relatively typical development and longer life expectancy.

Related Conditions

Other disorders caused by ESCO2 mutations include SC phocomelia syndrome and Juberg-Hayward syndrome (JHS). These conditions share many clinical features with Roberts syndrome, including limb shortening, cleft lip or palate, and growth delays.

JHS often presents with milder symptoms, and intellectual development can remain normal. It may also feature elbow joint fusion. Some researchers consider JHS a variant of Roberts syndrome, while others regard it as a separate condition, supported by studies such as Kantaputra et al. (2021). This variation highlights the importance of expert evaluation when ESCO2 mutations are identified, as clinical presentation alone may not fully define the diagnosis.

Cellular and Molecular Mechanisms

Roberts syndrome results from impaired cohesin function due to defective ESCO2. This leads to:

Premature separation of centromeres
Heterochromatin repulsion
Chromosomal instability
Higher rates of aneuploidy (extra or missing chromosomes)
Increased programmed cell death (apoptosis)

Interestingly, the syndrome shares similarities with thalidomide embryopathy, a condition linked to the drug thalidomide. Research suggests that thalidomide may suppress ESCO2 function, explaining the overlapping clinical features.

Epidemiology

Roberts syndrome is extremely rare. Fewer than 150 cases have been described in medical literature, but underdiagnosis is suspected due to the variability in symptom severity and overlap with other disorders. Cases have been reported worldwide, with no known sex or racial preference. However, higher incidence is observed in families with consanguinity, and founder effects in certain populations have led to more frequent identification of specific mutations, such as c.505C>T (p.Arg169Ter) in Colombia.

Symptoms

Symptoms usually appear before birth and are often evident at delivery. Severity ranges from life-threatening malformations to milder findings that may be overlooked until later in life.

Growth

Intrauterine growth restriction
Small birth size
Continued growth delays after birth

Limbs

Symmetrical limb shortening, often mesomelic (middle portion of limbs)
Severe shortening or absence of limbs (tetraphocomelia)
Underdeveloped or absent thumbs
Reduced numbers of fingers (oligodactyly)
Curved little fingers (clinodactyly)
Joint stiffness or contractures
Clubfoot (talipes equinovarus)

Facial Features

Cleft lip and palate, often bilateral
Microcephaly and micrognathia (small jaw)
Flat cheekbones (zygomatic hypoplasia)
Beak-like nose or underdeveloped nostrils
Downward slant of the eyes
Wide-set or protruding eyes
Small, low-set, or rotated ears

Neurological

Intellectual disability (ranging from mild to severe), though some individuals have typical intellectual development
Hydrocephalus or exencephaly in severe cases
Rare neurological complications such as cranial nerve palsy or moyamoya disease

Vision and Hearing

Corneal opacity
Small eyes (microphthalmia)
Cataracts or colobomas
Hearing loss

Cardiac

Congenital heart defects, including VSD, ASD, or PDA

Genitourinary

Kidney malformations, such as horseshoe kidneys or polycystic kidneys
Cryptorchidism or hypospadias in males
Genital anomalies in females, such as clitoral hypertrophy or uterine malformations

Skin and Other Findings

Sparse or light-colored hair
Hemangiomas
Café-au-lait spots or areas of hypopigmentation

Testing and Diagnosis

Diagnosis involves both genetic and cytogenetic evaluation.

Molecular Testing

Genetic sequencing, such as Sanger or exome sequencing, identifies ESCO2 mutations. Large deletions or duplications may require specialized copy number analysis.

Cytogenetic Analysis

Microscopic chromosome studies reveal the RS effect, including premature centromere separation and heterochromatin repulsion.

Prenatal Testing

Severe limb shortening, growth restriction, or cleft lip and palate detected by ultrasound may prompt genetic testing for confirmation.

Treatment and Management

There is no cure for Roberts syndrome. Management focuses on symptoms and improving quality of life, requiring a multidisciplinary approach. This often includes:

Surgery for cleft lip or palate and skeletal deformities
Physical, occupational, and speech therapy
Vision and hearing assessments with tailored interventions
Monitoring and care for cardiac and renal conditions
Infection prevention, particularly in newborns with facial malformations
Genetic counseling for families, including options for prenatal or preimplantation testing in future pregnancies

Prognosis

Outcomes vary significantly based on the severity of symptoms and organ involvement.

Severe cases may lead to significant complications before or shortly after birth, sometimes requiring immediate intensive care.
Milder cases allow for near-typical development with support, and some individuals live independent lives with normal intellectual function.

Differential Diagnosis and Genetic Interpretation

Detection of an ESCO2 mutation does not automatically confirm Roberts syndrome. Some variants may result in milder phenotypes or be associated with related conditions such as Juberg-Hayward syndrome. Proper interpretation requires input from genetic specialists to avoid misclassification and to guide accurate counseling and care.

Support for Families and Caregivers

Although Roberts syndrome can be overwhelming at the time of diagnosis, early intervention, therapy, and support significantly improve outcomes. Many children grow up to attend school and participate in family and community life. Some individuals remain undiagnosed until adulthood, particularly in milder cases. Access to knowledgeable medical teams and support networks helps families navigate both the medical and emotional challenges of the condition.

引用文献｜References

キーワード｜Keywords

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