Chung–Jansen syndrome

Chung–Jansen syndrome (CJS), also called PHIP–related disorder, is a dysmorphic syndrome genetic characterized by a variable delay in development and impaired intellectual development, as well as overweight or obesity, behavioural abnormalities (including hyperactivity, aggressive behaviour, anxiety, mood disorder or common features of autism spectrum) and facial dysmorphism (for example, high forehead, thick eyebrows and/or sinofris, upturned nose or voluminous ears, among other aspects). Other manifestations include hypotonia, ocular abnormalities, abnormalities of fingers and toes, joint hypermobility, or abnormal pigmentation. It is a rare congenital disorder, since the syndrome has currently been diagnosed in about 300 people worldwide, a number that is increasing.

The syndrome is named after the two doctors and researchers who have been doing separate research on this genetic variation. On the one hand, the American doctor Wendy Chung, whose laboratory is at the Columbia University Medical Center in the city of New York City (United States), who did a study on the syndrome in 2016 and in 2018 and 2019. On the other, the Dutch Sandra Jansen, who works at the AMC, which is the university hospital and Faculty of Medicine affiliated to the University of Amsterdam (The Netherlands), and together with his colleague Bert de Vries, published an article about the syndrome in 2017.

Features

Chung–Jansen syndrome is caused by a mutation heterozygous along the PHIP gene. The main traits displayed by people with this disorder are usually delayed development, behavioural problems and risk of obesity. Also, during childhood, they may have feeding difficulties, as well as delayed developmental milestones like rolling, crawling, standing straight and walking. The delay in motor development is partly related to low muscle tone, so it is common for them to complain of fatigue and they may even need aids such as a wheelchair. As for speech and fine motor skills, they are also frequently delayed.

On the other hand, during growth (especially during adolescence), behaviour problems appear. That is why they can be diagnosed with a developmental and/or behavioural disorder. There may also be problems with irrational fears (anxiety) and problems processing stimuli (sensory integration problems).

For their part, many children are overweight as they grow, a fact that may be associated with the use of medication, but also with the genetic abnormality. It is currently not known how the variation in the PHIP gene causes neurodevelopmental problems and obesity. However, as with any genetic disorder, the characteristics and severity of the problems can differ greatly from case to case.

Clinical signs and symptoms

The phenotypic description of this disease is based on an analysis of the biomedical literature and uses the terms of the Human Phenotype Ontology (HPO). Phenotypic abnormalities are presented in order of frequency of occurrence in the patient population:

• Very common:
  • Intellectual disability
  • Macrotia
  • Neurodevelopmental delay
• Frequent:
  • Abnormality of refraction
  • Anteverted nares
  • Attention deficit hyperactivity disorder
  • Broad nasal tip
  • Café au lait spots
  • Clinodactyly of the fifth finger
  • Fatigue
  • Feeding difficulties in infancy
  • high forehead
  • Hypermetropia
  • Hypertelorism
  • Hypotonia
  • Impulsivity
  • Increased body weight
  • Long philtrum
  • Synophris
  • Tapered finger
  • Thin vermilion border
• Occasional:
  • 2–3 toe syndactyly
  • Almond-shaped palpebral fissure
  • Constipation
  • Cryptorchidism
  • Epicanthus
  • Gait disturbance
  • Gastroesopageal reflux
  • Generalized joint laxity
  • Hand tremor
  • Neonatal hypotonia
  • Ptosis
  • Recurrent otitis media
  • Recurrent upper respiratory tract infections
  • Seizure
  • Sleep disturbance
  • Strabismus
  • Upslanted palpebral fissure

Psychological development and behaviour

behaviour problems are one of the most characteristic features of people with Chung–Jansen syndrome. Specifically, it refers to oppositional, defiant and sometimes even (verbally) aggressive behaviour that may be related to a developmental or behavioural disorder and/or learning delay. The following developmental and/or behavioural disorders may be present:

• ASD (Autism): Many children and adults have autistic features. Although the diagnosis of ASD (autism spectrum disorders) is not always made in children, their behaviour, fears and sensitivity to stimuli indicate it. Many parents, therefore, use educational methods made for people with autism (providing security, structure, etc.).

• ADHD / ADD: In the case of attention deficit hyperactivity disorder, children show difficulties concentrating and, sometimes, show hyperactive and impulsive behaviour. For these children, sitting still in class or doing tasks independently is difficult, as they are easily distracted. Children who do not display any hyperactive behaviour but have problems concentrating and learning may suffer from attention deficit disorder.

• DCD / Dyspraxia: Developmental coordination disorder causes difficulties in coordination and movement planning. This may have to do with fine and gross motor skills. In this way, carrying out tasks that are normal for children, such as learning to write, draw shapes, get dressed or eat with a knife and fork, are complex for them. In addition, they often move stiffly and have difficulty finding balance. However, this does not mean that they will not acquire it, but rather that they tend to learn these skills at a much slower pace and with more practice. The same thing happens in adults, a fact that can cause problems learning certain skills (such as learning to drive a vehicle).

In addition, the following disorders may also play a role within the syndrome:

• Anxiety disorder: Anxiety disorders are common in children and adults. Especially in childhood, when it is still difficult to differentiate fact from fiction, many children are afraid of many things, with the possibility of waking up at night because of fear or not sleeping well. For example, they may imagine things that are in their bedroom or they may be afraid of the dark.

• Oppositional defiant disorder / Conduct disorder: A large number of children display oppositional, defiant and/or (verbally) aggressive behaviour. This may be related to oppositional defiant disorder, but it may also be independent as part of conduct disorder. Children can easily get angry and have mood swings. In addition, they have difficulty regulating their emotions, so they often have tantrums that can even last a long time.

• Sensory processing disorder: Sensory processing may be different in people with the syndrome, as some do not respond appropriately to stimuli coming through their senses. In many cases, patients are hypersensitive to noises and crowded environments.

Learning

Chung–Jansen syndrome is associated with various learning difficulties and intellectual disabilities, as well as complications in acquiring gross and fine motor skills compared to other children of the same age. These are some of the consequences:

• Frustration: Children sometimes seem lazy and stubborn. The frustration of not being able to perform a certain task is often behind this behaviour, so these tasks must be explained several times so that children understand what is expected of them and how to complete them.

• Trouble speaking and acting: There is often a gap between verbal and stage skills. People with the syndrome are verbally well developed and can express themselves correctly, but use words that are not appropriate for their age. But they have more problems with performance skills, which include organization and visuospatial function. Because of this, their abilities are overestimated, which can increase behavioural problems and fatigue.

• Cognition: Diagnosing cognitive abilities in young children can be difficult due to additional issues such as ADHD and fatigue. It can be hard for them to focus and keep their attention on the things they are being asked to do. When tested, most children's IQs are around 80, with rising and falling peaks. On a socio-emotional level, they are often much younger than their chronological age.

• Education: School can be a great challenge for children with Chung–Jansen syndrome. Extra help and support is often needed. If this is not feasible, children may go to special education where more attention is paid to the specific problems the child is dealing with.

• Daily life: Most young adults live with their parents, a small number live with others or independently with outpatient support. There are also adults who are married and have children.

Physical problems

Although physical problems do not predominate in this syndrome, there are limitations:

• Overweight: Most people with Chung–Jansen syndrome are overweight or obese. The reason is currently unclear, although there may be a relationship between the PHIP protein and the leptin-melanocortin pathway, which is important for satiety and energy balance. Furthermore, it could also be caused by the side effects of medication use.

• Low muscle tone (hypotonia): In infancy, certain milestones are reached later than the average child. For example, not being able to raise the neck correctly in the prone position, having difficulty rolling over, sitting up, crawling, standing and walking. Once the child is able to walk, gross motor skills will continue to be a challenge, as children often have a rigid gait pattern and tire easily. Important milestones like cycling and swimming are usually achieved later.

• Eye problems: Often there is an abnormality of the eyes, such as squint, poor vision and cataracts.

• Gastrointestinal problems: Another common problem is constipation. The intestines work more slowly, which makes it difficult for many children to go to the bathroom and learning to go to the bathroom is more difficult.

• Skeletal problems: Some children are born with an abnormality in the hip, called hip dysplasia. Often the femoral head and socket are malformed and a retractor or surgery is needed to position the hip correctly. Due to low muscle tone, there is a risk of scoliosis as children get older. This implies a lateral curvature of the spine. Many people have joint hypermobility, which can cause pain and increase fatigue.

• Abnormalities and problems with the kidneys: Urinary tract infections occur frequently in young children. Some people have congenital abnormalities of the kidneys, such as a horseshoe kidney, where the kidneys have grown together or a person is born with only one kidney. Other problems that can occur are: high concentration of calcium in the urine, kidney stones or swelling of the kidney due to accumulation of urine.

Inheritance

Chung–Jansen syndrome is caused by a defect in the PHIP gene encoding the pleckstrin homology domain-interacting protein. The PHIP gene is located on chromosome 6 (6q14.1). Individuals normally have two chromosome 6s with two copies of the PHIP gene. People with Chung–Jansen syndrome have a defect in one of the two copies, called a heterozygous variant. This can be a variant in the coding sequence of the gene or a deletion of the gene or part of it. This is called autosomal dominant inheritance.

Most people with the syndrome are the first one in the family and their parents do not have the variant. The variant had arisen during the formation of reproductive cells (eggs and sperm) or in early fetal development. Sometimes the variant is inherited from one of the parents.

Often, if the variant is inherited, the parents do not know they are carriers. This becomes clear when blood tests are done after the child has been diagnosed. In the case of inheritance, there is a 50% chance that children will acquire the disorder.

It is currently unknown how the defect in PHIP causes neurodevelopmental problems and overweight.

Therapy

Socio-emotional development

Children with Chung–Jansen syndrome have an overall delay in their social-emotional development compared to their peers. Therefore, they often find it difficult to connect with other children their own age. This is because their behaviour differs from what can normally be expected at that age. This is often related to a developmental or behavioural disorder and learning difficulties. Many times, they have multiple diagnoses, such as ADHD, ASD, anxiety, depression, learning disabilities and sensory processing disorder.

Many children with the syndrome react differently to certain situations (such as setbacks and unexpected events) and the intensity of their emotions is stronger. Their emotional regulation often does not work well and sometimes they show extreme reactions of anger, joy and sadness. Temper tantrums or meltdowns can also last longer and are present in older children.

For emotional regulation, there are some useful resources such as: pictograms, emotion and stimulus meters so that children can indicate to what extent they are angry, sad or overstimulated; a separate room or space for the child to calm down or rest; drawings (drawing situations or emotions can help children clarify certain situations); books / courses on ADHD, ASD, behaviour problems or sensitivity to stimuli; an extremely predictable daily routine/schedule and/or medication.

For all these reasons, learning strategies to regulate positive and negative emotions is very important, but equally difficult since sometimes there is less emotional control. Young patients often need help learning to recognize emotions in others, but also their own, for which an occupational therapist can be helpful. Likewise, the participation of a psychologist is recommended to carry out neuropsychological tests, make diagnoses and support adults or parents in the education of the child (especially in the treatment of rebellious and disruptive behaviours). Often the medication is prescribed by a psychiatrist.

Similarly, for the treatment of anxiety (often part of ASD) a psychologist can also use cognitive behavioural therapies or EMDR. In any case, applying methods intended to deal with a child with ASD can be of great help. Attention is required to provide security, structure and clarity. An autism expert or outpatient care may be helpful to provide support at home.

Cognitive development

For children diagnosed with Chung–Jansen Syndrome, the learning process is more difficult and less smooth compared to "neurotypical" children, due to problems with attention and stimulus processing. The main focus sometimes has to be on "learning to learn".

For these children it is very beneficial to repeat the instructions several times and break the larger tasks into several smaller subtasks to keep an overview of the situation. This will help the child understand the expected result. Generally speaking, children with Chung–Jansen syndrome have good verbal abilities, but completing tasks can be difficult.

Support

In case of early diagnosis, the step-by-step learning method can be applied at a very young age. Outpatient support specialists can educate and assist parents in helping the child through the use of developmentally oriented materials.

The importance of early diagnosis is also related to the choice of education. Although some children diagnosed with Chung–Jansen receive a mainstream education (often with additional support), many others benefit from special education, as it is more appropriate in relation to physical disabilities and/or associated with the syndrome.

Motor and language development

Gross motor skills

Many children and adults with Chung–Jansen syndrome have hypotonia, or low muscle tone. This causes a global delay in development. A physiotherapist is very important for the stimulation of gross motor skills (sitting, crawling, walking, etc.). Because developmental delay is often seen in early childhood, a physical therapist is often involved from infancy.

Commonly used medical aids are: braces, arch supports/orthopedic shoes, spreader pants for hip dysplasia or wheelchair.

Fine motor skills

For children with Chung–Jansen, occupational therapists are often called upon to stimulate fine motor skills (using fingers/hands with eye–hand coordination). The therapist can practice with children, for example, cutting, colouring, drawing and writing. The occupational therapist can also offer specific help to promote children's self-sufficiency, such as teaching them to dress and undress. In addition, this professional is often involved as an external expert in regular education, but also works in a special education program or in a rehabilitation center.

Commonly used fine motor aids are: spring scissors or pencil grip.

Language

A speech therapist takes care of stimulating speech, which can be delayed in children with Chung–Jansen syndrome. They can also give advice on problems with eating (oral motor skills). For example, many young children with the syndrome struggle to drink adequately from the breast or bottle. Likewise, chewing and swallowing food regularly causes problems, such as choking. This also has to do with low muscle tone. However, it has been observed that these problems tend to improve as the child matures.

Although it takes longer than usual, speech develops normally in most children with Chung–Jansen syndrome, but unfortunately some remain nonverbal.

Commonly used speech aids are: pictograms, speech computers or feeding pumps / feeding tube.

Sensory information processing

Abnormalities in sensory information (SI) processing may be related to ASD and ADHD/ADD, but may also be independent. In Chung–Jansen syndrome, atypical sensory experiences may be part of a complex and coherent system of problems. Patients may show signs of hypersensitivity (under or over stimulation) to the following senses:

• Vision (visual).
• Smell (olfactory).
• Taste (gustatory).
• Feeling (tactile).
• Hearing (auditory).
• Balance (vestibular).
• Posture and sense of movement (proprioception).
• Internal organs (interocepsis).

Patients can experience stimuli in a hypersensitive (overstimulation) or hyposensitive (understimulation) way and they can perceive more or less information from the environment. As a result, your reaction to the environment may be unexpected or inappropriate. Common problems in people with this syndrome are:

• Hypersensitivity to noise.
• Hypersensitivity to temperature.
• Hypersensitivity in the mouth to temperature and texture.
• Hypersensitivity to balance.
• Abdominal complaints.

For all this, children with sensory processing problems can receive help from a physical therapist, an occupational therapist or a speech therapist who specializes in this area. The therapist can develop a sensory profile showing hypersensitivities or hyposensitivities to the various senses. Based on this, the child is treated with games and exercises.

In addition to therapy, it will be necessary to teach the child to deal with his processing of stimuli (reduce, avoid stimuli) and to pay attention to the regulation of the emotion he/she feels in this process. For this, there are resources such as:

• Chewing necklace or other fidgets.
• Headphones/earplugs.
• Weighted materials such as weighting pillows and blankets.
• Pressure vest.
• Other sensory materials such as shaving foam, sand, rice, etc.
• Pictograms/daily structure charts.