Verheij Syndrome

Verheij Syndrome

Article
Ear, Nose, & Throat (ENT)
Brain & Nerve
+11
Contributed byKrish Tangella MD, MBAOct 08, 2021

What are the other Names for this Condition? (Also known as/Synonyms)

  • PUF60 Gene Syndrome
  • PUF60-Related Syndrome

What is Verheij Syndrome? (Definition/Background Information)

  • Verheij Syndrome is a rare genetic abnormality that involves the PUF60 gene located on the long arm (q) of chromosome 8, specifically in the q24.3 region. In this disorder, either the gene function is disrupted, or the gene is missing, resulting in a set of associated signs and symptoms that typically include speech and learning challenges, physical growth and development delays, and behavioral issues
  • Since the PUF60 gene is involved, the disorder is also known as PUF60-Related Syndrome. This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). Verheij Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed
  • Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment may involve physician experts from several specialties, and can include the use of speech and language therapy, physiotherapy, and surgery for correction of physical defects
  • The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Verheij Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets Verheij Syndrome? (Age and Sex Distribution)

  • The incidence of Verheij Syndrome is presently unknown. It is an extremely rare and recently described disorder
  • In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
  • Verheij Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
  • Both males and females may be affected
  • Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Verheij Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Verheij Syndrome.

  • In some individuals, a positive family history may be an important risk factor for the condition
  • Currently, no environmental and lifestyle (including dietary) factors have been implicated
  • The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Verheij Syndrome? (Etiology)

Verheij Syndrome is caused by abnormal changes/mutations to the PUF60 gene located in the long arm (q) of chromosome 8, specifically in the band q24.3.

  • The changes result in abnormal functioning of one of the two copies of the gene leading to associated signs and symptoms. In some cases, one copy of the gene on chromosome 8 may be missing or absent
  • The PUF60 gene, or poly (U) binding splicing factor 60 gene, is important for a variety of processes such as splicing and transcriptional regulation. In case of any disruption in gene function, faulty instructions translated into messages are conveyed causing a wide variety of associated signs and symptoms
  • Apart from deletion of the PUF60 gene, it may also undergo certain changes, when it is termed as a pathogenic variant. According to medical literature, around 25 cases of PUF60 variants are reported. The exact medical implication of this variant is not well-understood; however, individuals with PUF60 variants are known to present milder symptoms than those with PUF60 gene deletions

The amount of missing chromosome material may also vary from one individual to another resulting in a variable set of signs and symptoms.

  • In general, there are two chromosomes numbered 8. Children with PUF60-Related Syndrome typically will have one (chromosome 8) in normal condition, while the other is abnormal. The abnormality is characterized by a loss of chromosomal material
  • Most cases of the disorder develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material at 8q is observed in either of the parents
  • However, in rare cases, the disorder may be inherited. When inherited, the condition is transmitted in an autosomal dominant manner

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

A chromosome deletion disorder indicates that a certain portion of the chromosomal material is missing, which may be detected through molecular genetic testing. Depending on the nature and amount of material deleted, the manifestation of a set of signs and symptoms are noted.

What are the Signs and Symptoms of Verheij Syndrome?

The signs and symptoms of Verheij Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material deleted and the number of genes affected. As a general rule, a small loss of chromosome material generally results in milder signs and symptoms. Conversely, larger deletion of the chromosome material generally results in severe signs and symptoms. It is important to note that exceptions may also occur, where individuals with small amount of chromosomal loss, may have disproportionately severe presentations.

The commonly noted signs and symptoms of Verheij Syndrome include:

  • Mild developmental delays; delays in milestone achievement such as for rolling, sitting, crawling, and walking
  • Small-sized head (microcephaly)
  • Short stature
  • Abnormal facial features are not very pronounced, but may include asymmetry of the face, increased facial hair, thin upper lip, skin tags on the face and neck region, etc.
  • Skeletal abnormalities that may include hands and feet deformities and abnormal spinal curvature
  • Many children have loose joints (joint laxity)
  • Seizures may affect some children
  • Heart defects such as valve defects, coarctation of the aorta, and tetralogy of Fallot, are commonly noted
  • Kidney anomalies may include absent kidney and horseshoe-shaped kidneys
  • Vision impairment due to structural eye defects, such as coloboma and strabismus (squint), may be observed. Some children present shortsightedness or longsightedness
  • Feeding difficulties due to swallowing difficulties, vomiting, and gastroesophageal reflux disease (GERD), in a few children
  • Hearing impairment from glue ear (fluid buildup in the middle ear) or narrow ear canal
  • Speech, language, and communication difficulties
  • Behavioral problems may include aggressive behavior, mood swings, and self-injurious behavior
  • Major neurological signs and symptoms are not usually noted

How is Verheij Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider Verheij Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

Verheij Syndrome is diagnosed on the basis of the following information:

  • Complete physical examination and thorough medical history evaluation, including family medical history
  • Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
  • Hearing assessment through various tests including:
    • Otoscopy: Examination using an instrument that allows the physician to look inside the ear
    • Weber test: A test in which a vibrating tuning fork is placed on the midline of the head
    • Rinne test: A test in which a vibrating tuning fork is held next to the ear and then in front of the ear, until the individual no longer hears the sound
    • Audiometric test: Hearing tests that involve listening to different tones
  • Eye and vision assessment through:
    • General eye exam
    • Visual acuity test using a special and standardized test chart (Snellen chart)
    • Refraction studies using various instruments
    • Fundoscopic (ophthalmoscopic) examination by an eye specialist, who examines the back part of the eye (or the fundus)
    • Slit-lamp examination
  • Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
  • Radiological studies of the affected regions, as needed
  • Evaluation of heart defects through:
    • Chest X-rays
    • Echocardiogram
    • Electrocardiogram (EKG)
    • Cardiac catheterization
    • Fetal ultrasound for heart defects
  • Neurological examination that involves the central nervous system (brain and spinal cord)
  • Behavioral studies
  • Prenatal studies including abdominal ultrasonography
  • Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
    • Fluorescence in situ hybridization (FISH) testing
    • Array comparative genomic hybridization (array-CGH)
    • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Verheij Syndrome?

The complications of Verheij Syndrome may include:

  • Severe emotional stress for parents and caregivers
  • Pregnancy complications
  • Severe heart and kidney abnormalities causing impaired function of the organs
  • Difficulty in standing and walking due to scoliosis and other bone abnormalities
  • Developmental abnormalities that can affect day-to-day activities
  • Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Verheij Syndrome Treated?

There is no cure for Verheij Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, ophthalmologists, otolaryngologists, neurologists, internists, cardiologists, endocrinologists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for Verheij Syndrome may involve:

  • Use of hearing aids; in case of fluid buildup in the middle ear, some children may require the placement of a small ventilation tubes to help with improved fluid drainage
  • Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet: Seizure control is important to ensure that the child’s learning ability is not significantly affected
  • Employing suitable learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
  • Speech and language therapy; the use of sign language may be beneficial
  • Physiotherapy for weakened muscles, including incorporating daily exercise regimen
  • Development of motor skills via daily exercises, swimming, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
  • Use of walking aids including foot orthotics and special footwear
  • For feeding difficulties, use of feeding tubes (temporary), medications, feed thickeners, including special diets and nutritional supplements. A surgical procedure named fundoplication may be necessary in some children with severe gastroesophageal reflux disease (GERD)
  • Surgical correction of heart and other physical defects, as assessed by a healthcare expert
  • Use of suitable glasses and surgical rectification of vision defects, if necessary
  • Use of padded brace for abnormal spinal curvature and posture management, including surgical correction of severe cases. Also, children may be provided specially designed furniture, such as chairs, tables, and beds, for spine support while sitting and sleeping
  • Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
  • Occupational therapy

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can Verheij Syndrome be Prevented?

Verheij Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. A majority of cases are sporadic occurrences, which means there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a familial history:

  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

It is important to note that the chances of both the parents with normal chromosomes having another child with Verheij Syndrome is highly unlikely. This may be confirmed via specialized prenatal testing and preimplantation genetic diagnosis (PGD), if needed. Prenatal tests may include chorionic villus sampling (CVS) and amniocentesis.

What is the Prognosis of Verheij Syndrome? (Outcomes/Resolutions)

The prognosis of Verheij Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook.

  • Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
  • Some children may require extended medical support and care

Additional and Relevant Useful Information for Verheij Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/

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Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

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