History
Causes and symptoms
Epidemiology
Case reports
Diagnosis and treatment
References
Further reading
C syndrome, also known as Opitz trigonocephaly syndrome (OTCS) or C Syndrome, is a rare and heterogeneous genetic disorder with a broad range of severity. It was first documented in 1969.
C syndrome. Image Credit: nobeastsofierce/Shutterstock.com
C syndrome consists of trigonocephaly and dysmorphic craniofacial features as the hallmark features. In the literature, there are just about 60 cases of this syndrome. OTCS's vast clinical range overlaps with that of other clinical entities, further complicating the diagnosis.
OTCS is linked to a high rate of mortality. Almost half of all OTCS patients die within the first year of life. However, some patients may have a high quality of life.
History
Opitz et al. (1969) were the first to describe a brother and sister with a malformation syndrome characterized by atypical facial features, polydactyly, heart abnormalities, and cryptorchidism in the male child.
Sargent et al. (1985) documented 12 trigonocephaly instances, six of which were coupled with additional abnormalities. When viewed from above, the forehead is narrow and pointed, and it is frequently connected with biparietal widening and a triangular shape of the skull.
Several chromosomal disorders have been linked to trigonocephaly. Sargent et al. (1985) presented a case with first-cousin parents and two afflicted siblings.
Three unrelated patients were described by Lalatta et al. (1990). One of the women had a significant omphalocele. Another case of massive omphalocele associated with the C syndrome was reported by de Almeida et al. (1992).
Causes and symptoms
OTCS does not have a common genetic cause. Changes (mutations) in the following genes have been linked to this syndrome in recent research: MAGEL2, ASXL3, FOXP1, and IFT140.
Some cases carry chromosomal abnormalities, like deletion and trisomy in chromosome 3, or deletion, partial trisomy, and reciprocal translocation in other chromosomes. Until recently, it was considered that OTCS was inherited in an autosomal recessive fashion. However, de novo dominant inheritance or gonadal mosaicism is currently thought to be the cause of the illness.
Clinically, OTCS is quite variable, with a wide range of severity. It is characterized by a significant developmental delay. However, there have been reports of instances with mild to normal intelligence. One of its key characteristics is trigonocephaly, which, while not exclusive, has become essential and definitional of OTCS.
The disease is also marked by a unique set of facial dysmorphisms, including unusual nose and ocular anomalies, many of which may be traced back to the trigonocephalic sequence.
Oral malformations, such as changes of the upper lip and philtrum, large alveolar ridges with rugose anterior palatal mucosa, high-arched palates, and tooth malposition, are more particular to OTCS patients and can contribute to mastication and feeding issues.
Patients with OTCS often have anteverted nares, cryptorchidism, biparietal constriction, a flattened nasal bridge, and epicanthus. Internal malformations, particularly heart problems, are also prevalent (present in one-half of OTCS cases). Frequently, abnormal lobulations of the lungs and kidneys, as well as abnormalities of the pancreas and liver, are documented.
Female pseudohermaphroditism, gingival overgrowth, and hypoplasia of the ear cartilage are also commonly observed. Occasionally, patients with OTCS can also exhibit cleft palate, congenital diaphragmatic hernia, constipation, toe, and hand polydactyly. Many of the patients had epileptic fits at some point during their lives. Usually, pregnancies are uneventful, however, anhydramnios caused by renal anomalies or some of the most serious congenital defects can be discovered by ultrasonography.
Epidemiology
In the literature, there are only about 60 cases, most of which are single case reports or tiny series.
Case reports
Medics presented the case of a Caucasian male newborn who died at the age of five months after having his craniofacial abnormality surgically corrected.
The patient was a Caucasian baby who was born at 39 weeks to non-consanguineous parents. This was a 30-year-old mother's first pregnancy with a bicornuate uterus. Early intrauterine growth retardation complicated the pregnancy, although the antenatal ultrasound assessment was otherwise normal.
The labor and delivery happened on their own. At one and five minutes, the Apgar score was 9 and 10, respectively.
Micrognathia, upslanting eyelids, hypotelorism, depressed nasal bridge, and low-set ears were all present at birth, as were additional dysmorphic craniofacial features: micrognathia, upslanting eyelids, hypotelorism, depressed nasal bridge, and low set ears.
Ultrasounds of the heart and kidneys came back normal. The early closure of the metopic suture was confirmed by computed tomography.
During the first four months of life, there was no evidence of a psychomotor delay; nonetheless, fidgety activity was absent. A normal 46 XY karyotype was discovered through chromosome research. They also used a single-nucleotide polymorphism (SNP) array but found nothing meaningful.
During surgery to address the craniofacial deformity, the baby died unexpectedly at the age of five months. Except for a twin left renal artery, an autopsy revealed no further defects that would have changed the clinical presentation. Around the brain arteries, several microcalcifications were discovered.
Diagnosis and treatment
OTCS is a clinical diagnosis based on the characteristics already mentioned. As this condition can be caused by several genes (and chromosomal anomalies), whole-exome sequencing (WES) can be utilized to uncover the underlying molecular etiology in certain people who have been clinically diagnosed with it.
Although there is no specific treatment for OTCS, it is possible to treat some of the symptoms. When trigonocephaly is severe, surgery to relieve pressure on the brain and improve facial look may be required.
Other surgical procedures for heart and other anomalies may be required. Some individuals may benefit from supportive therapies such as speech therapy and interdisciplinary rehabilitation.
Although the majority of the cases are sporadic, there have been a few reports of family occurrences. Recurrence in sibs with unaffected parents suggests that germinal mosaicism may be the source of familial instances.
Following reports of recurrence in siblings, future pregnancies in afflicted families should be closely watched. Patients and their families can benefit from genetic counseling.
References
- Urreizti R, Grinberg D, & Balcells S (2019). C syndrome-what do we know and what could the future hold? Expert Opinion on Orphan Drugs, 7(3), 91-94. doi: 10.1080/21678707.2019.1589448. https://www.tandfonline.com/doi/full/10.1080/21678707.2019.1589448
- Urreizti R, Damanti S, Esteve C, et al. (2018). A De Novo FOXP1 Truncating Mutation in a Patient Originally Diagnosed as C Syndrome. Scientific Reports, 8(1), 694. doi:10.1038/s41598-017-19109-9. https://www.nature.com/articles/s41598-017-19109-9
- Travan L, Pecile V, Fertz M, et al. (2011). Opitz trigonocephaly syndrome presenting with sudden unexplained death in the operating room: a case report. Journal of Medical Case Reports, 5, 222. doi:10.1186/1752-1947-5-222. https://pubmed.ncbi.nlm.nih.gov/21689463/
- C syndrome. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/5978/c-syndrome
- C syndrome. [Online] Orpha Net. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=1062&Disease_Disease_Search_diseaseGroup=opitz-c-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)%20concerned=C-syndrome--Opitz-trigonocephaly-syndrome-&title=C-syndrome--Opitz-trigonocephaly-syndrome-&search=Disease_Search_Simple
- C Syndrome. [Online] NORD. Available at: https://rarediseases.org/rare-diseases/c-syndrome/
- C SYNDROME. [Online] OMIM. Available at: https://www.omim.org/entry/211750
Further Reading