NORD gratefully acknowledges Mounya Duggal, MDCM Candidate, McGill University School of Medicine, and Roser Urreizti, PhD, Biochemistry Laboratory and Neurometabolical Diseases Unit, Institut de Recerca Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain for assistance in the preparation of this report.
C syndrome, also known as Opitz trigonocephaly syndrome (OTCS), is a complex condition defined by a broad group of clinical features and abnormalities. Children may be given this preliminary diagnosis and later diagnosed with a specific genetic condition. Affected children are born with a malformation in which the head is a triangular shape due to premature union of the skull bones (trigonocephaly), a narrow pointed forehead, a flat broad nasal bridge with a short nose, vertical folds over the inner corners of the eyes, an abnormal palate that is deeply furrowed, abnormalities of the ear, crossed eyes (strabismus), joints that are bent or in a fixed position, and loose skin. Developmental and learning disabilities are common. These signs and symptoms can vary significantly from one patient to another.
OTCS is a heterogeneous disorder, which means that it does not have a single cause. Changes (mutations) in multiple and distinct genes, combinations of genes and chromosomal abnormalities may be the underlying cause this condition.
In 1969, John Marius Opitz, a German-American medical geneticist, was treating two siblings, one brother and one sister. He noticed similar features: trigonocephaly, facial dysmorphia and severe mental delay. The syndrome was first named “C syndrome of multiple congenital abnormalities”, where the “C” stood for this family’s surname. Then, it was renamed C syndrome, Opitz C syndrome or Opitz trigonocephaly syndrome.
One of the major features of OTCS is a condition in which the skull is a triangular shape. This occurs due to premature closure of the bones (trigonocephaly or prominent metopic suture due to its premature fusion). Patients with this disorder also have a distinct face in which the nasal bridge is broad with a short nose, there are vertical folds over the inner corners of the eyes (epicanthus) and paralysis of facial muscles (facial palsy). These children may have abnormalities of the outer ear, crossed eyes (strabismus), thin upper lip, smooth vertical groove between the base of the nose and the border of the upper lip (philtrum),an undersized jaw (micrognathia), a short neck and loose skin. Additional characteristics can include abnormalities of the breastbone (sternum), webbed fingers and/or toes (syndactyly), short limbs, heart, pancreas, kidney and lung abnormalities and failure of one or both testicles to move down into the scrotum (cryptorchidism).
Feeding difficulties may occur because of a deeply furrowed palate in the mouth and malposition of teeth. Additional characteristics can include loss of muscle tone and joints in the hands bent in a fixed position or dislocated.
Affected children may have central nervous system malformations and seizures. Developmental delay (motor, mental or global) and speech delay are common and children with C syndrome have intellectual disability that can vary from mild to severe.
There is no common genetic cause for OTCS. Recent research has found that changes (mutations) in specific genes could be associated with this condition: MAGEL2, FOXP1, IFT140 and ASXL3.
Until recently, OTCS was thought to follow an autosomal recessive pattern of inheritance. However, it is now believed that the disorder occurs as a result of de novo dominant heritance or gonadal mosaicism. Mosaicism refers to a condition in which a person has cells that differ from each other in genetic makeup.
Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from an affected parent or can be the result of a new change (mutation) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Only about 60 patients with OTCS have been reported in the world’s medical literature. OTCS is a very rare disorder that seems to affect males and females in equal numbers. The prevalence is between 1/800,000 and 1/1,000,000.
OTCS is a clinical diagnosis based on the features mentioned earlier. Since multiple genes (and chromosomal abnormalities) may be associated with this condition, whole exome sequencing (WES) can be used to identify the underlying molecular cause in some patients clinically diagnosed with this condition.
There is no specific treatment for OTCS but treatment for some symptoms is possible. When trigonocephaly is severe, surgery may be performed to relieve the pressure on the brain and improve facial appearance. Other surgical procedures may be indicated for heart and other malformations. Supportive therapies such as speech therapy and interdisciplinary rehabilitation may be helpful in some patients. Genetic counseling is recommended for patients and their families.
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