Clinical characteristics.

CTCF-related disorder is characterized by developmental delay / intellectual disability (ranging from mild to severe), with both speech and motor delays being common; feeding difficulties, including dysphagia, and other gastrointestinal issues (gastroesophageal reflux disease and/or irritable bowel syndrome) that can lead to growth deficiency; hypotonia; eye anomalies (strabismus and/or refractive errors); scoliosis; nonspecific dysmorphic features; sleep disturbance; tooth anomalies (crowded teeth and/or abnormal decay); and, less commonly, other congenital anomalies (cleft palate, gastrointestinal malrotation, genitourinary anomalies, and congenital heart defects, including aortic ectasia). Short stature, seizures, hearing loss, recurrent infections, microcephaly, and autistic features have also been described in a minority of affected individuals. At least four reported individuals with CTCF-related disorder developed Wilms tumor, one of whom had bilateral Wilms tumor. However, there is no clear evidence of a significant predisposition for the development of cancer in individuals with CTCF-related disorder at this time.

Diagnosis/testing.

The diagnosis of CTCF-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CTCF identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy with a low threshold for clinical feeding evaluation and/or radiographic swallowing study for those with clinical signs or symptoms of dysphagia; gastrostomy tube placement may be required for persistent feeding issues. Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation. Conductive hearing loss may respond to placement of PET; hearing aids may be helpful per otolaryngologist. Standard treatment for developmental delay / intellectual disability, neurobehavioral issues, gastroesophageal reflux disease, strabismus, refractive errors, ptosis, cleft palate, dental anomalies, scoliosis, hip dysplasia, ankle/foot anomalies, sleep disturbance, recurrent infections, renal anomalies, anomalies of the genitalia, congenital heart defects, seizures, and Wilms tumor.

Surveillance: At each visit: measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for gastroesophageal reflux disease and/or constipation; assess for new manifestations such as seizures or changes in tone; monitor developmental progress and educational needs; assess for behavioral issues or changes in behavior; monitor for signs/symptoms of sleep disturbance; assess for frequent infections. Assess for signs and symptoms of scoliosis at least annually until skeletal maturity. Dental and ophthalmology evaluations at least annually or as clinically indicated. Annual audiology evaluation through childhood or as clinically indicated. No tumor screening protocol for individuals with CTCF-related disorder has been developed.

Pregnancy management: In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to or during pregnancy may be possible.

Genetic counseling.

CTCF-related disorder is inherited in an autosomal dominant manner. Approximately 80% of individuals with CTCF-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CTCF pathogenic variant. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the CTCF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CTCF-related disorder should be considered in probands with the following clinical findings and family history.

Clinical findings

• Mild-to-profound developmental delay (DD) or intellectual disability (ID)

AND

• Any of the following features presenting in infancy or childhood:
  • Hypotonia
  • Feeding difficulties
  • Slow growth
  • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors
  • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia
  • Sensorineural or conductive hearing loss
  • Nonspecific dysmorphic features (See Clinical Description.)
  • Cleft palate
  • Congenital heart defects
  • Tooth anomalies, such as crowded teeth and abnormal decay
  • Genitourinary anomalies
  • Sleep disturbance
  • Recurrent infections
  • Seizures

Family history. Because CTCF-related disorder is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CTCF-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CTCF identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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. (2) Identification of a heterozygous CTCF variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of chromosomal microarray analysis (CMA) or a multigene panel. Note: Single-gene testing (sequence analysis of CTCF, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes CTCF and other genes of interest (see _{Differential Diagnosis}) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants 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. Of note, given the rarity of CTCF-related disorder, some panels for intellectual disability 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.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of CTCF pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.
  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.

Clinical Description

To date, more than 100 individuals have been identified with a pathogenic variant in CTCF [Valverde de Morales et al 2023].

Developmental delay (DD) and intellectual disability (ID). The vast majority of affected individuals have developmental delay and intellectual disability, ranging from mild to severe.

• About 65% of affected individuals have been reported to have speech delay, ranging from mild delay to individuals who are nonverbal. The mean age of saying the first word is 20 months, with a range of 10 months to 5 years.
• About 53% of affected individuals have been reported as having motor delay, with 10/42 (24%) of reported individuals having coordination or balance issues.
  • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months.
  • Mean age of walking independently is 18 months, with a range from 12 months to 42 months.
  • At least one affected individual was nonambulatory at age 17 years.

Neurobehavioral/psychiatric manifestations. The most common neurobehavioral manifestations are autism spectrum disorder / autistic features and attention-deficit/hyperactivity disorder, although most affected individuals do not have either of these findings. Less frequent behavioral/psychiatric manifestations may include:

• Aggression
• Anxiety
• Difficulty regulating emotions
• Destructive behaviors
• Oppositional behaviors
• Self-injurious behaviors

Hypotonia has been described in just under half of affected individuals. Hypotonia may contribute to both motor and feeding issues.

Gastrointestinal/feeding. Infant feeding difficulties are common. Contributing factors may include dysphagia, cleft palate, and hypotonia. A minority of affected individuals have required placement of a feeding tube (see Management).

• Feeding problems are most commonly reported in early infancy, with some individuals experiencing resolution of feeding problems at older ages, most with the removal of their feeding tube.
• About 17% of affected individuals experience constipation.
• Other reported functional gastrointestinal complications include gastroesophageal reflux disease, dysphagia, and irritable bowel syndrome.
• Gastrointestinal malformations may include intestinal malrotation and rectal duplication.

Growth. In affected individuals, weight is the most consistently impacted growth parameter, with about 29% of affected individuals demonstrating low weight (2 standard deviations below the mean for age and sex). In initial publications [Gregor et al 2013], microcephaly and short stature were listed as characteristic features of individuals with CTCF-related disorder; however, only about one fourth of affected individuals have short stature (24/102) and/or microcephaly (27/102).

Facial features. No consistent dysmorphic features have been observed across described individuals with CTCF-related disorder to suggest a recognizable facial phenotype. If present, dysmorphic features are nonspecific. Individuals with CTCF-related disorder can commonly demonstrate widely spaced and/or deep-set eyes, broad nasal bridge, broad nasal tip, and thin vermilion of the upper lip.

Ophthalmologic involvement. Strabismus or refractive errors were found in more than half of individuals. While strabismus is the most commonly reported issue, other reported problems include:

• Hypermetropia
• Astigmatism
• Amblyopia
• Myopia
• Ptosis

Hearing impairment has also been reported in affected individuals. Both unilateral and bilateral hearing loss have been reported. Hearing loss may also be sensorineural and/or conductive in nature. Many reported individuals with CTCF-related disorder who have hearing loss have benefited from the use of hearing aids (see _Management).

Craniofacial/dental. About one quarter of affected individuals have been reported to have a cleft palate, and about one third of affected individuals have been found to have dental anomalies unrelated to cleft palate. Other reported dental issues include:

• Impacted teeth
• Increased incidence of dental decay
• Ectopic teeth
• Absent secondary teeth
• Abnormal shape of teeth
• Discoloration of teeth
• Midline misalignment

Musculoskeletal features have been reported in approximately half of affected individuals. Scoliosis is the most common finding and tends to be static. Less common findings include:

• Kyphosis
• Vertebral compression fractures, most typically in older individuals
• Hip dysplasia
• Pes valgus
• Bilateral clubfeet
• Genu valgum
• Calcaneus valgus
• Tight tendons requiring tenotomies
• Finger abnormalities, such as camptodactyly

Sleep disturbance. About one third of affected individuals have been reported to have issues with sleep. In some affected individuals this may manifest as delayed sleep onset (difficulty falling asleep), while in others it can present as frequent awakenings. Some affected individuals have benefited from pharmacologic therapy, including melatonin or clonidine (see Management).

Recurrent infections. To date, 27 individuals with CTCF-related disorder have been reported to have recurrent infections [Gargallo et al 2022, Valverde de Morales et al 2023]. Recurrent respiratory infections, urinary tract infections, otitis media, and impetigo are some of the most commonly reported findings. One affected individual has low IgA levels [H Li, personal observation].

Genitourinary abnormalities have been documented in about one quarter of reported individuals. While renal anomalies were reported in both males and females, anomalies of the genitalia were most often reported in males [Gargallo et al 2022, Valverde de Morales et al 2023].

• Renal findings include:
  • Dysplastic kidney
  • Solitary kidney
  • Polycystic kidney
  • Renal ectasia
  • Vesicoureteral reflux disease
  • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor
• Anomalies of the genitalia in males can include:
  • Cryptorchidism
  • Spermatocele
  • Penile chordee
  • Phimosis
  • Hypospadias
• In females, hypoplastic labia majora has been noted.

Cardiac findings. Congenital heart defects were reported in 22 affected individuals. Reported findings include [Gargallo et al 2022, Valverde de Morales et al 2023]:

• Atrial septal defects
• Tetralogy of Fallot
• Pulmonary valve stenosis
• Patent ductus arteriosus
• Mild aortic coarctation
• Aortic ectasia (Aortic rupture has not been reported to date in individuals with this condition, although data on progression of this finding is limited.)
• Bicuspid aortic valve

Seizures are a less common finding in affected individuals, with fewer than 20% experiencing seizures. In those who do have seizures, there is no consistent seizure type. Similarly, there is no consistent age of onset for seizures, with onset ranging from early infancy to primary school age (age ~6 years) to adolescence (one individual had initial seizure at age 15 years). Reported seizure types include:

• Febrile seizures
• Generalized tonic-clonic seizures
• Tonic seizures
• Petit mal seizures

Neuroimaging. Brain MRI has been normal in most affected individuals who have undergone imaging; however, some individuals have nonspecific findings, such as white matter abnormalities, gray matter heterotopia, focal polymicrogyria, periventricular leukomalacia, focal simplified gyration, thin corpus callosum, and prominent lateral ventricles. One affected individual was reported to have mild but progressive cerebellar and cerebral atrophy [Valverde de Morales et al 2023].

Malignancy. At least four reported individuals with CTCF-related disorder developed Wilms tumor, with ages at diagnosis being one, two, four, and five years, respectively. One affected individual had bilateral Wilms tumor [Konrad et al 2019, Gargallo et al 2022, Valverde de Morales et al 2023]. However, there is no clear evidence of a significant predisposition for the development of cancer in individuals with CTCF-related disorder at this time. Therefore, no tumor screening protocol for individuals with CTCF-related disorder has been developed.

Prognosis. It is unknown whether life span in CTCF-related disorder is abnormal. More than 16 adult individuals with CTCF-related disorder have been reported in the literature, with the oldest individual being age 34 years at the time of the report [Valverde de Morales et al 2023], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been identified [Valverde de Morales et al 2023].

Prevalence

CTCF-related disorder is a rare disorder. Though the prevalence is unknown, 107 individuals from different countries (Canada, China, Denmark, England, France, Israel, Italy, Japan, Norway, Spain, United Arab Emirates, and United States) have been reported in the literature [Gargallo et al 2022, Temple et al 2022, Chen et al 2023, Lyu et al 2023, Valverde de Morales et al 2023]. As most reported affected individuals have been diagnosed recently using whole exome sequencing, this condition is likely underdiagnosed and underreported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CTCF-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CTCF-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

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

Pregnancy Management

Limited data is available on pregnancies for women with CTCF-related disorder.

In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to or during pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

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

Mode of Inheritance

CTCF-related disorder is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 80% of individuals with CTCF-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CTCF pathogenic variant [Valverde de Morales et al 2023].
• To date, nine individuals diagnosed with CTCF-related disorder inherited a CTCF pathogenic variant from a typically asymptomatic parent. Two of the transmitting parents were mosaic for the detected pathogenic variants [Valverde de Morales et al 2023].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with CTCF-related disorder may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the CTCF pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Valverde de Morales et al 2023].
• If the parents have not been tested for the CTCF pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CTCF-related disorder because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with CTCF-related disorder has a 50% chance of inheriting the CTCF pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CTCF pathogenic variant, the parent's family members may be at risk.

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 genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CTCF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

Transcriptional repressor CTCF (CTCF; also called CCCTC-binding factor) is a DNA-binding transcription factor that plays a critical role in regulating gene expression and chromatin organization [Phillips & Corces 2009]. CTCF contains 727 amino acids and three functional domains: an N-terminal domain (residues 1-267), a central DNA-binding domain with 11 tandem Cys2-His2 (C2H2) zinc fingers (ZFs) (residues 268-577), and a C-terminal domain (residues 578-727). The ZFs largely orchestrate the interaction between CTCF and specific DNA sequences that are found throughout the genome. The RNA-binding domain (RBD) of CTCF interacts with RNA as well. CTCF can function as a transcriptional activator or repressor, depending on its binding location and iterating partners. CTCF organizes the three-dimensional structure of the genome by forming DNA loops and facilitating the formation of higher-order chromatin structures for proper cellular function and development. In addition to its role in chromatin organization, CTCF is involved in genomic imprinting, DNA methylation patterning, X-chromosome inactivation, and alternative splicing [Kung et al 2015, Hashimoto et al 2017, Hansen et al 2019, Saldaña-Meyer et al 2019, Alharbi et al 2021].

Missense pathogenic variants account for more than half of reported pathogenic variants. The majority of pathogenic missense variants are located in ZFs, particularly in the DNA-binding region and less commonly in other functional domains, such as the RBD and Tyr-Asp-Phe (YDF) domains [Valverde de Morales et al 2023].

Mechanism of disease causation. Loss of function

Author Notes

The Emory CTCF-related disorder center (www.ctcfemory.com), led by Dr Hong Li and Dr Victor Corces, is devoted to understanding the phenotypic spectrum, natural history, and molecular mechanism of CTCF-related disorder. For information about ongoing research studies, contact _{[email protected]}.

Acknowledgments

We would like to thank all the families and their clinicians who have contributed to ongoing Emory CTCF-related disorder research (www.ctcfemory.com). We would also like to thank the CTCF-related disorder patient support group for all their contributions in helping us understand more about the natural history of this condition.

Revision History

• 25 April 2024 (ma) Review posted live
• 7 June 2023 (hl) Original submission

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