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Crouzon Syndrome
Crouzon Syndrome is a rare disease.
The clinical features of this Crouzon syndrome characterized by craniosynostosis and facial hypoplasia.
Synonyms
Crouzon craniofacial dysostosis
How common is Crouzon Syndrome?
This condition affects approximately 1 to 9 in 1000000
The estimated prevalence in the general population of Europe is 0.9 in 100,000
The incidence of this condition is estimated at 1 : 25,000 births.
This disease accounts for 4.5% of all cases of craniosynostosis
Over half of Crouzon syndrome cases occur as new, spontaneous mutations.
The birth prevalence of this condition is estimated to be 16.5 per million births
33% to 56% of these cases, may arise as a consequence of spontaneous mutations, with the remaining being familial.
Inheritance
The inheritance pattern of this condition is Autosomal dominant
The disease is transmitted in an autosomal dominant manner with variable penetrance and highly variable expressivity.
Age of onset of this condition
- Infancy
- Neonatal
What are the symptoms of Crouzon Syndrome?
Very Common Symptoms
- Abnormal facial shape
- Abnormal skull morphology
- Frontal bossing
- High forehead
- Multiple suture craniosynostosis
Common Symptoms
- Arnold Chiari malformation
- Brachycephaly
- Cerebellar hypoplasia
- Conductive hearing impairment
- Conjunctivitis
- Hypertelorism
- Hypoplasia of the maxilla
- Increased intracranial pressure
- Midface retrusion
- Proptosis
- Ptosis
- Strabismus
- Turricephaly
Occasional Symptoms
- Abnormal sacrum morphology
- Acanthosis nigricans
- Amblyopia
- Choanal atresia
- Convex nasal ridge
- Headache
- Hearing impairment
- Hydrocephalus
- Hypopigmented skin patches
- Iris coloboma
- Melanocytic nevus
- Narrow internal auditory canal
- Narrow palate
- Optic atrophy
- Respiratory insufficiency
What are the Clinical Features of this condition?
Craniosynostosis is variable but many sutures are usually involved.
The facial dysmorphology is characterized by ocular hypertelorism, small beaked nose, proptosis, exophthalmos, hypoplastic maxilla and mandibular prognathism.
Germline mosaicism has also been proposed in families with two unaffected parents who had more than one affected child
The synostosis is evolutive and is usually either not visible or only slightly visible at birth. It usually manifests by the age of 2 years and becomes progressively more severe.
However, precocious and congenital forms have been reported in which hypoplasia of the upper maxilla is pronounced and leads to respiratory difficulties, and the exophthalmia is severe resulting in palpebral malocclusion.
Hydrocephaly, descent of the cerebellar tonsils and anomalies in jugular venous drainage are also frequently observed in Crouzon disease and may pose therapeutic problems.
Two thirds of patients with Crouzon disease have intracranial hypertension, which may lead to blindness.
What are the causes of this condition?
Crouzon disease is caused by mutations of the fibroblast growth factor receptor FGFR2 (10q25.3-q26) with 80% being located to the immunoglobulin (Ig)-like domain III (IgIII domain) of the extracellular region and an additional 20% of mutations being located in the IgI-IgII domains, transmembrane and tyrosine kinase regions.
A distinct form of Crouzon disease associated with acanthosis nigricans has been reported and is caused by a specific mutation (p.Ala391Glu) in the transmembrane domain of another protein from the same family, FGFR3 (Crouzon syndrome – acanthosisnigricans;).
Moreover, mutations in ERF (19q13.2) gene encoding the ETS2 repressor, resulting in anosteogenic stimulation, have been associated to a Crouzon-like syndrome.
Thirty to sixty percent of mutations resulting in Crouzon syndrome are sporadic, and there is likely an association with increased paternal age
How is this diagnosed?
- Patients with Crouzon syndrome may have a “cloverleaf skull/Kleeblattschädel” orientation of the cranium in severe cases, as is observed in this case. This is due to premature fusion of multiple sutures, which always coincides with some element of bilateral coronal craniosynostosis, leading to a shortened AP diameter of the cranial vault.
- Diagnosis can be suggested at birth by assessing key morphologic cranial and facial features.
- Genetic testing and molecular analysis are often required to confirm the diagnosis, as in the case presented.
- It is not unusual for more mildly affected family members to go undiagnosed until the birth of a more severely affected child.
How is this treated?
Surgical interventions are aimed at preventing cerebral, ophthalmological or respiratory complications and correcting the cranio-facial dysmorphy.
The craniofacial surgical approach adopted needs to take into account both the cranial and facial synostosis and should be tailored to each patient.
What is the prognosis of this condition?
The Intelligence is usually normal with appropriate management.
Differential Diagnosis
- The primary differential diagnosis for Crouzon syndrome are the other acrocephalosyndactyly disorders. These diseases are characterized by calvarial synostoses/syndactyly and include:
- Type 1: Apert syndrome: Characterized by skull and limb malformations and occurs due to a defect in the FGFR2 gene; presents with the classic triad of brachycephaly, facial hypoplasia, and syndactyly
- Type 2: Apert-Crouzon syndrome: See above
- Type 3: Saethre-Chotzen syndrome: Characterized by growth delays, short stature, and cranial/ocular/hand defects
- Type 4: Goodman syndrome: Characterized by marked malformations of the head and face, abnormalities of the hands and feet, and congenital heart disease
- Type 5: Pfeiffer syndrome: Characterized by premature synostosis, syndactyly, and/or wide and deviated thumbs or big toes
