August 12, 1998
Dear Opitz C Families:
I am writing you from the North of Germany where it has been a rainy summer. I am still feeling moved by the wonderful conference in Salt Lake City this past June. It was a great pleasure to meet you, such gracious parents and terrific kids. As you know, Alexis Poss asked me to write a short summary of the C-syndrome lecture because it was not possible to make transcripts. Actually, this is a very hard thing for me to do because I am afraid the summary will appear unfeeling and technical, rather than reflect the love and intensity I felt during our meeting. Please forgive me.
Introduction
It was nearly 30 years ago in 1969 that John Opitz, Ronald Johnson, Samuel McCredie, and David Smith reported on two siblings with a new, undescribed syndrome of multiple congenital anomalies. These sibs had a characteristic appearance with trigonocephaly (this means a prow-shaped forehead), ear anomalies, a flat nose, strabismus, epicanthal folds, multiple bucco-labial frenula, micrognathia, short stature (especially short limbs), postaxial hexadactyly (that means an extra pinkie on the hands and feet), loose skin, joint contractures and dislocations, and joint crepitation. The syndrome was named the C syndrome according to the first letter of the surname of this family. Today the term Opitz trigonocephaly is often used as a synonym, paying tribute to the most common symptom and to Dr. Opitz as the first author of the original paper.
There are not enough patients known to fully define the spectrum of the condition, from the most severely affected to the most mildly affected. It is important to consider that there are 61 conditions described with trigonocephaly, of which the C syndrome is only one. Unfortunately some of these different syndromes have phenotypes that overlap widely. Nineteen of these syndromes can be detected by testing the chromosomes for abnormalities. Several others can generally be ruled out because they are associated with exposure to certain drugs.
To date, there are about 30 cases reported in the medical and genetic literature, as well as about 25 cases known to Dr. Opitz because they were sent to him for consultation. Reviewing these cases it seems that while they share trigonocephaly and a wide variety of additional malformations, the differences between the children suggests that the underlying condition is not always the same (they are not all C syndrome). Ten years ago Dr. James Reynolds recognized this problem and suggested distinguishing cases as either [1] the C syndrome or [2] the C phenotype, meaning that they (those with the phenotype) are dissimilar from the original patients although they share some physical anomalies.
The Diagnosis
The diagnostic criteria for C syndrome are expected to become clearer once we know the gene responsible for the C syndrome so that we can test children suspected of the diagnosis to uncover all of those who truly have the syndrome. Unfortunately at this time we are still in the beginning stages of finding the gene. Once we know the gene and its function, we can proceed to understand the causes and mechanisms of the syndrome.
Although not every symptom is found in every patient, there are some key symptoms that are used to make the diagnosis since they are found in most, if not all, patients. In the C syndrome the primary physical anomaly is the trigonocephaly, a triangular shape to the head when seen from above. This skull configuration comes from the prominent forehead which, in turn, is caused by a ridged metopic suture. A suture is the place where the bones of the skull meet. The metopic suture is one of the main skull sutures extending from the front of the "soft spot" on a baby’s head to the nose. Normally sutures remain open until the skull has reached a final adult head size, at which point they close (synostosis). However, in most cases of trigonocephaly this suture closes prematurely, often before birth. Although it has not been proven I suspect there is also premature synostosis of small sutures affecting the shape of the face. I feel that the typical small nose with anteverted nostrils, low nasal bridge, upslanting palpebral fissures, fleshy epicanthal folds, bitemporal narrowing, and typical palate are all secondary effects of the premature closure of the bones between the midface and the base of the skull. If you can imagine the effects on a balloon in which one part is pinched and the opposite side expands, you have the idea behind these secondary effects of a premature cranial synostosis.
In addition to the trigonocephaly other characteristic anomalies of the C syndrome are the multiple buccolabial frenula (folds of skin that attach the inside of the lip to the gums) and ear and brain anomalies. The ears appear low-set on the face, tilted backward, and soft – which suggests to me that there is a defect of ear cartilage. Indeed, a cartilage defect would seem to explain some other symptoms of the C syndrome such as the joint dislocation, hyperextensibility and crepitation (crackling produced by irregular cartilage surfaces rubbing together), which is mostly found in the hips, knees, and elbows. Cartilage is a connective tissue like skin, bones, and blood vessels (arteries/veins). So perhaps it is not a surprise that the kids are small for their age and have small hands and fingers (the effect of a bone problem); and we find loose redundant skin (a skin problem); persistent fetal lymphedema (a lymphatic vessel problem), and a frontal capillary hemangioma (a blood vessel problem) in most cases.
Along with the premature cranial synostosis of the metopic suture and the connective tissue anomalies, the central nervous system is involved in the syndrome. Children with the C syndrome may have agenesis of the corpus callosum, although other brain malformations have been described. Agenesis of the corpus callosum means that the bundle of nerves that connect the hemispheres of the brain never formed. Functionally, we can attribute findings such as hypotonia (muscle weakness), strabismus, developmental delay, mental retardation, sucking/swallowing problems, and reflux/vomiting to neurological dysfunction. It is important to remember that the degree of neurological dysfunction is variable, with some children demonstrating an outcome better than expected from the available literature. It is interesting to note that the defects in the C syndrome tend to be located in the midline of the body, such as the agenesis of the corpus callosum, bulging forehead, small nose, typical palate, sternum anomalies, diastasis recti, cryptorchidism, and sacral dimple.
Using the diagnostic criteria above, one can distinguish atypical cases such as patients with long fingers instead of short ones, or downslanting palpebral fissures instead of upslanting, etc. It may turn out that these patients have the classic C syndrome because we may learn that the phenotype is highly variable. However, in this heterogeneous group of the C phenotype (according to James Reynolds) we found some patients similar to each other, but different from the classic C syndrome. So, it makes for good clinical sense to create several "C syndrome-like" groups to test the hypothesis of heterogeneity, i.e. as to whether there are several genetically different forms of the C syndrome.
The most common questions
In the eyes of many physicians, craniosynostosis requires craniotomy. The assumption is that developmental delay and mental retardation are caused by craniosynostosis leading to microcephaly (a small head because the brain could not grow after the sutures closed) leading to pressure on the brain (because a normal-sized brain is growing in a too-small head). This said, in the C syndrome the major sutures are open with the exception of the metopic suture. Thus the skull does grow, leading to the typical trigonocephaly configuration. Despite this, most patients with C syndrome have microcephaly. We suspect that the brain is biologically a small brain, not small because it is confined. To date there is no evidence that craniotomy has any effect on developmental outcome. Given this, it would seem that the only effect of the craniotomy is a cosmetic one (which could be important for some families). It is important to bear in mind, however, that three cases known to us had to have repeat craniotomies because of a rapid reclosure of the metopic suture after surgery. It may be that there is a "genetic plan" for the premature synostosis.
If there is no evidence of a growth hormone deficiency, the answer is no. Of course children who are treated with growth hormone may grow faster for a while, but most will stop growing earlier than expected, reaching the same adult height as they would have without the growth hormone therapy.
The sucking and swallowing difficulties may be of neurological origin. These problems existed before birth and may have resulted in polyhydramnios (an excess of amniotic fluid in the womb). The placement of a gastric tube should make feeding much easier for everyone. In most cases maturation slowly improves this problem.
Muscle weakness of the diaphragm and sphincter of the stomach may cause the frequent vomiting. If there is true reflux, a Nissan fundoplication may be very helpful.
Yes! In our experience with the C syndrome there seems to be a general maturational delay. This means that all the neurological symptoms should improve and the outcome will be better than anticipated as a newborn. Moreover, the child’s receptive skills may be better than you would expect based on your child’s expressive responses. Don’t be overly concerned with the diagnosis; rather care for the special needs of your child as you have done so wonderfully until now. Also, until proven otherwise, a 25% recurrence risk is to be anticipated after the birth of a first affected child. Except for ultrasound surveillance, at the moment there is no effective prenatal diagnostic test.
With all good wishes and many thanks for the conference, I remain
Faithfully yours,
Dipl.-Med. Axel Bohring