FG Syndrome: Causes, Symptoms & Treatment

FG syndrome is an X-linked abnormality. Affected individuals suffer from defective vitamin D receptors and, as a result, multifaceted symptoms such as developmental delay, muscle weakness, strabismus, and sensorineural hearing loss. Treatment is symptomatic.

What is FG syndrome?

Chromosomal aberrations are also called chromosomal abnormalities. They are structural or numerical changes in chromosomes in an organism or a particular cell. Chromosomal aberrations are therefore major changes within the genome that can cause serious medical conditions. One structural chromosomal abnormality is FG syndrome, also known in the literature as Opitz-Kaveggia syndrome or Keller syndrome. The disorder is a severe and rare condition caused by abnormalities of the X chromosome and results in developmental delays in addition to physical abnormalities. The first description of the disease was made in 1974. John Marius Opitz and Elisabeth Kaveggia are considered the first describers. The name FG syndrome has its roots in an acute case of the syndrome. The letters F and G are the initials of last names of two sisters who gave birth to several children with the syndrome. Allelic links exist between FG syndrome and Lujan-Fryns syndrome, according to current evidence. The prevalence for FG syndrome is estimated at one case in 500 newborns. Heart defects and limb defects are also not excluded.

Causes

FG syndrome is caused by mutations in the MED12 gene, better known as mediator complex subunit 12. The gene is located at gene locus 13.1 of the X chromosome and carries 44 exons. The unit encodes in DNA for a subunit of the mediator complex, also known as mediator or thyroid hormone receptor-associated protein. Other names include TRAP or thyroid hormone receptor-associated protein, vitamin D receptor interacting protein, and DRIP and vitamin D receptor-interacting protein. The protein gene product consists of 28 subunits. In the case of a structural abnormality of the corresponding chromosome, the composition of the protein changes structurally so that the complex no longer fulfills its physiologically intended functions and a defective vitamin D receptor is formed. Different subtypes of FG syndrome exist, depending on the exact gene locus of the chromosomal abnormality. In addition to locus Xq13, abnormalities have been documented in FLNA Xq28, Xp22.3, CASK Xp11.4-p11.3, and Xq22.3. Based on the observed familial disposition, x-linked hereditary basis is suggested.

Symptoms, complaints, and signs

Patients with FG syndrome are conductively symptomatic of mental retardation. In most cases, multiple personality changes are also present. A strong tendency toward hyperactivity has been observed in virtually all cases. Accompanying symptoms may include facial abnormalities. For example, the patients’ facial features often appear inanimate and unfriendly. In many cases, there is low muscle tone throughout the body. The corners of the mouth droop accordingly and motor function may be impaired. In some cases, a permanently open mouth has been observed, also due to reduced muscle tone. Symptoms of the digestive tract have also been documented. Chronic constipation is one of the most important symptoms in this context. In isolated cases, patients have been found to have foramen parietale permagnum (FPP). This is a rare disorder of cranial development associated with bone defects of the parietal bone and significant enlargement of the parietal foramina. The respiratory tract of many patients is also susceptible to infection. In addition, cleft palate, laryngeal clefts, strabismus, hernias, hypospadias, hydroceles, sleep apnea, and sensorineural hearing loss, as well as recurrent otitis or reflux, may be signs of FG syndrome.

Diagnosis and course

The first suspected diagnosis of FG syndrome is made in infancy or early childhood. Usually, clinical symptoms such as decreased muscle tone, permanently open mouth, and chronic constipation provide the first clues to the syndrome. The physician obtains proof of the reduced muscle tone through neuroelectrical examinations.Molecular genetic methods are used to confirm the diagnosis and provide evidence of the causative chromosomal abnormality. Mild variants of GBBB syndrome, Atkin-Flaitz syndrome, fragile X syndrome as well as Keipert syndrome, naso-digito-acoustic syndrome and Say-Meyer syndrome are to be differentiated as differential diagnoses. The same is true for Donnai-Barrow syndrome, Sotos syndrome, and C syndrome. Pelizaeus-Merzbacher disease, Dubowitz syndrome, and Renpenning syndrome are also possible differential diagnoses. Suspicion can be raised prenatally in malformation ultrasound. Patients with FG syndrome have an unfavorable prognosis. Many affected individuals die during childhood. After the critical childhood period, few of the patients die.

When should you see a doctor?

Parents who notice malformations, signs of chronic constipation, and other evidence of FG syndrome in their child should take it to a pediatrician. X-linked anomaly is a serious condition that definitely needs to be diagnosed and treated. Therefore, unusual complaints, external abnormalities and other symptoms should be clarified by a doctor. Should serious complications arise, the best case is to contact the emergency medical service or the child should be taken to a hospital immediately. Patients suffering from FG syndrome must be closely monitored and regularly examined. Depending on the severity of the abnormality, treatment may need to be provided by multiple physicians. For example, in the case of hearing problems, an ear specialist must be consulted, while in the case of vision problems, an ophthalmologist or optometrist is the right person to contact. The doctor in charge is best able to answer the question of which medical professionals should be consulted in detail. In most cases, he will also recommend therapeutic counseling to the parents and initiate the necessary support for the child.

Treatment and therapy

A causative treatment is not yet available for FG syndrome. Because it is a genetic disorder, advances in gene therapy may eventually provide causal treatment options within the next few decades. At present, patients with the syndrome are treated purely symptomatically. Therapy of the life-threatening symptoms is the focus of treatment measures. Especially possible cardiac defects have to be corrected invasively. Surgical treatment measures are also available for cleft palate, cleft larynx, reflux, hernias, strabismus, hypospadias, and hydrocele. A feeding tube may be required to ensure nutritional status. CPAP ventilation is used for sleep apnea. Sensorineural hearing loss is treated with cochlear implants. Recurrent otitis is treated with tubes to equalize pressure. Growth hormone therapy can counteract severe growth disorders. On the supportive therapeutic side, parents of affected children receive psychological guidance. Mental retardation is therapeutically counteracted by means of early intervention.

Outlook and prognosis

FG syndrome offers an unfavorable prognosis. The affected children often die during infancy. If the first years of life are survived, there is a high chance of survival. However, the symptoms considerably impair the well-being and the general quality of life of the sufferers. Therefore, psychological treatment must always be initiated during therapy. This can at least improve the mental well-being. Nevertheless, FG syndrome is a serious disease that represents a great burden for those affected. Above all, mental retardation has a negative impact on health, as it is accompanied by numerous neurological complaints. Concomitant symptoms such as constipation or foramen parietale permagnum can lead to further complications in the course of life, from which the sufferers may die. Life expectancy is reduced and most sufferers die either in childhood or between the ages of 40 and 50. The reduced mobility can cause bed confinement, obesity, and many other secondary symptoms and long-term effects that further worsen the health of those with the disease. Early therapy can alleviate symptoms and allow patients to live a relatively normal life in a care facility.

Prevention

To date, FG syndrome can be prevented exclusively by genetic counseling during family planning and, if necessary, fine ultrasound during pregnancy. The decision not to have a child of one’s own is considered the most effective and, to date, the only preventive measure if there is an appropriate family history.

Follow-up

In most cases, the options for follow-up care in FG syndrome are severely limited. Because it is a genetic disorder, it cannot be completely or causally treated. In order to prevent inheriting FG syndrome to the children, genetic counseling should be performed if the child is desired. Self-cure cannot occur in this disease. Most of the affected persons depend on surgical interventions to alleviate the symptoms. Patients should take it easy after such an operation and not engage in any physical activity. In general, physical exertion or other stressful activities should be avoided. Furthermore, patients are often dependent on taking hormones to promote growth. Care must be taken to ensure that these hormones are taken correctly and, above all, regularly, and possible side effects or interactions must also be taken into account. Therefore, a doctor should always be consulted if there is any uncertainty. Parents must pay particular attention to their children taking the medication correctly. Since the FG syndrome can also often lead to psychological complaints in the parents or in the relatives, they should also consult a psychologist.

What you can do yourself

The options for self-help in FG syndrome are limited. Those affected depend on treatment from a doctor to limit symptoms. As the children suffer from increased retardation, they need strong support and encouragement in their lives. This has to be done mainly by their own parents and relatives. This can minimize further complications in adulthood. Hyperactivity can also be treated by special training. Since many patients also suffer from vision problems, visual aids should be worn at a young age. This can prevent further deterioration of vision. Reflux disease should also be diagnosed and treated at an early age in order to avoid a possible ulcer or tumor. However, parents often need psychological support as well. This can take place through a psychologist or through discussions with other affected persons. The regular intake of growth hormones can also reduce disturbances in growth and thus in development. FG syndrome cannot be prevented directly. However, prenatal examinations can indicate the syndrome at an early stage.