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At a glance

An inherited polymalformative syndrome with congenital triangular-shaped head, combined with cardiac, digestive, and skeletal anomalies.

Synonyms

Opitz Trigonocephaly Syndrome; Trigonocephaly “C” Syndrome; Trigonocephaly Syndrome.

History

First described in 1969 by J.M. Opitz, a contemporary German-American geneticist. The “C” in the name of this syndrome refers to the initial of one of the first patients originally described by Opitz.

Incidence

The estimated prevalence is approximately 1 in 1,000,000. Around 60 cases have been described in the literature.

Genetic inheritance

C Syndrome is a genetically heterogeneous disease and its mode of inheritance is under debate. Autosomal dominant, autosomal recessive, and germline mosaicism as well as sporadic (de novo mutations) have been suggested. At least some cases were found to be associated with mutations in the CD96 Antigen (CD96) gene, which has been mapped to chromosome 3q13.1-q13.2. Few cases may be attributed to mutations in the MAGE-like 2 (Melanoma Antigen-like 2; MAGEL2) gene on chromosome 15q11.2.

Diagnosis

Based on the clinical findings of skull malformations combined with peculiar facies (narrow, pointed forehead, flat and broad nasal bridge with a short nose, epicanthus) and multiple cardiac, digestive, and skeletal anomalies.

Clinical aspects

These patients may present with failure to thrive secondary to generalized hypotonia and a poor sucking reflex. The main features involve the head and neck (trigonocephaly (due to metopic craniosynostosis), progressive microcephaly, biparietal widening of the head, upslanted palpebral fissures, epicanthal folds, strabismus, short nose with a broad and depressed nasal bridge, anteverted nares, micrognathia/retrognathia, high arched and deeply furrowed palate, thick anterior alveolar ridges, multiple buccal frenula, micro- or macrostomia, and low-set and posteriorly rotated ears) and short neck with redundant nuchal skin. Brain anomalies may consist of agenesis of the corpus callosum, occasionally polymicrogyria, cerebellar heterotopia, ☞Dandy-Walker Syndrome or hydrocephalus. Neurological findings include psychomotor retardation (may be severe), hypotonia (may later change to hypertonia), and seizures. Cardiovascular lesions are present in about half of the patients (eg, tetralogy of Fallot, ventricular septal defect, common truncus arteriosus, atrioventricular canal, subaortic stenosis, interrupted aortic arch, patent ductus arteriosus, pulmonary hypertension, Eisenmenger Syndrome, abnormal origin of right coronary artery, hypoplastic branch pulmonary arteries, or internal and external carotid arteries arising separately from the aortic arch. Abnormal segmentation of the lungs and severe lung hypoplasia have been described. Gastrointestinal anomalies (eg, visceral angiomatosis, omphalocele, umbilical and inguinal hernias, unexplained hepatomegaly, recurrent pancreatitis with ☞Caroli Syndrome, or malrotation), genitourinary tract anomalies (eg, prominent clitoris and labia majora, cryptorchidism, dilated ureters and hydronephrosis, renal cortical cysts, large multicystic kidneys and rarely unilateral renal agenesis, horseshoe kidney, agenesis of bladder with unilateral renal, Fallopian tube, and uterine agenesis), and skeletal anomalies (short stature (mainly due to short limbs), hyperextensible joints (later often changing to contractures, ...

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