Treacher Collins syndrome: Genectis and OSAS

Treacher Collins syndrome (TCS) is a rare congenital craniofacial
disfigurement. Its deformities can range from a slight defect of the cilia to
severe defects such as micrognatia and zygomaticotemporomaxillary dysostosis.
As well as mandibular hypoplasia and the underdevelopment of the auricles, the
downslant of the eyelids, coloboma of the eyelids and hypoplasia of the
zygomatic bone and lateral orbital wall are common features of this condition.
The disease always occurs bilaterally and affects males and females equally.
TCS patients are characterized by a normal intelligence level.
Genetics
TCS is an autosomal dominant disorder of craniofacial development with an
incidence of 1 in 50,000 live births. In more than 60% of cases there is no
previous family history and the condition is thought to arise as the result of
a de novo mutation. Loss-of-function mutations in the TCOF1 gene have been
demonstrated to underlie TCS. Although most cases of TCS can be diagnosed
clinically, the variable expression observed in this condition, together with
the high rate of new mutations may present the clinician with diagnostic
difficulties. Up to now mutation analysis of the TCOF1 gene has resulted in the
identification of over 120 different mutations that are spread throughout the
gene.
Recently, molecular analysis has been used to facilitate both prenatal and
postnatal diagnosis in families with a history of TCS. In a subset of these
families, TCS was diagnosed in the proband, but the status of the parents could
not be established unequivocally on the basis of clinical examination alone. In
these families, molecular analysis determined that one parent carried the
mutation, resulting in a 50% recurrence risk in future patients. So diagnosing
TCS genetically is becoming more important both prenatally and postnatally.
OSAS
Children and adults diagnosed with TCS are at risk for obstructive sleep apnea
syndrome (OSAS). OSAS is defined as a disorder of breathing during sleep,
characterized by prolonged partial upper airway obstruction and/or intermittent
complete obstruction that disrupt normal ventilation. Clinical symptoms of OSAS
are snoring, difficulty in breathing and apnea during sleep, but these symptoms
are often not recognized by patients, parents or physicians. Only the newborns
with TCS and overt obstructive breathing are recognized as such. Routine
screening for OSAS has never been part of the treatment plan for these
patients. Leaving OSAS untreated may result in major physical and functional
impairment due to the disturbed sleep patterns, for instance failure to thrive,
recurrent infections, feeding difficulties, disturbed cognitive functions,
attention deficits, delay of development, cor pulmonale, hypertension,
pulmonary hypertension, coronary artery disease, cerebrovascular disease and
sudden death. OSAS in non-syndromal patients is associated with a high BMI,
however there is a clinical impression that patients with TCS have a low BMI,
probably due to the extra effort necessary for respiration during the night
and/or metabolic changes. Studies have demonstrated that non-syndromal patients
diagnosed with OSAS have increased circulating levels of multiple biomarkers of
both systemic and local inflammation such as interleukin 6, tumor necrosis
factor α (TNFα) and C-reactive protein (CRP). Thereby OSAS in non-syndromal
patients often coexists with the metabolic syndrome. However, effective
treatment of OSAS is associated with a fall in cholesterol levels.Treatment
options for OSAS vary from wearing an orthognatic device during the night,
giving oxygen, nocturnal non-invasive ventilation, adenotonsillectomy,
tracheostomy or surgical advancement of the maxilla.

Primary objectives:
1. To analyze the exact pathogenic mutations in the TCOF1 gene in TCS
2. To determine the severity, prevalence, natural course within the cohort
TCS patients and potential metabolic and physical effects of OSAS in TCS

Secondary objective:
1. To design a treatment protocol for TCS with respect to screening for OSAS

This is a observational prospective, descriptive study. All patients diagnosed
with TCS that have been/are under treatment in the Erasmus MC or Erasmus MC -
Sophia Children*s Hospital will be included.
This study contains one cohort.

Investigation:
1 polysomnography in 1 night at home + venapuncture at the outpatient clinic +
3 questionnaires
Time schedule:
1 night at home + 10 minutes for visiting the outpatient clinic + 10 minutes
for filling out the questionnaires

The polysomnography has nog risks or complications, it is a non-invasive
investigation. Venapuncture will is not likely to have great risks. In total 5
tubes will be collected.

In conclusion: The risks are nihil for both parts of the investigation
Genetic outcome will not have any consequences for the severiity, prognose and
treatment of the patient. Whenever OSAS is detected there will be an appropiate
(mostly non-invasive) multidiscipline treatment available.