Genetics of Crouzon Syndrome

Updated: Dec 05, 2018
  • Author: Marie M Tolarova, MD, PhD, DSc; Chief Editor: Maria Descartes, MD  more...
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Overview

Practice Essentials

Severe cases of craniosynostosis syndromes, such as Crouzon syndrome, do not present diagnostic problems. More diagnostically challenging, however, are patients with Crouzon syndrome who demonstrate mild or no dysmorphology in infancy, especially when Crouzon syndrome is absent in parents and other relatives. Therefore, abnormal head shape in infants and even slight facial dysmorphology need to be followed up.

When diagnosed, an infant needs to be referred to a craniofacial center with a track record for treating syndromic craniosynostoses. Multidisciplinary management is critical, especially because surgeries and other procedures are time sensitive. A medical geneticist should be involved through the duration of all treatments.

Crouzon syndrome is named after the French neurologist Louis Edouard Octave Crouzon (1874-1938), who had a deep interest in hereditary neurologic diseases. He described the syndrome as hereditary dysostosis craniofacialis, detailing its presence in a mother and her son, both of whom had a triad of craniofacial deformities, facial anomalies, and exophthalmos.

Crouzon syndrome belongs to a large and heterogeneous group of conditions presenting with craniosynostosis, a common symptom of which is early fusion of one or more cranial sutures. Craniosynostoses have an estimated prevalence of 1 in 2100 to 2500 live births. [1, 2] The major division among craniosynostoses is between the nonsyndromic and syndromic forms. The syndromic forms, which are hereditary, make up 15-30% of all cases. [2] Crouzon syndrome accounts approximately for 4.8% of all cases of craniosynostosis, with the estimated birth prevalence ranging widely, from 1 in 25,000 in early studies [3] to 1 in 60,000 in later studies. [4, 5]

Inheritance of Crouzon syndrome is autosomal dominant, with complete penetrance and variable expressivity. [6] In about 25% of cases, a negative family history of Crouzon syndrome is observed, with the condition in these instances presumably arising from a fresh mutation.

Crouzon syndrome involves premature synostosis of coronal and sagittal sutures, starting in the first postnatal year. Once closed, the sutures have restricted growth potential. Premature fusion of skull base sutures is often seen in cases of multiple sutural synostoses, with the resulting occurrence of midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, exophthalmos, maxillary hypoplasia, and occasional upper airway obstruction. [7]

Unlike some other forms of autosomal dominant craniosynostosis, no digital abnormalities are present in Crouzon syndrome. See the image below.

Child with Crouzon syndrome. Note midfacial hypopl Child with Crouzon syndrome. Note midfacial hypoplasia, proptosis secondary to shallow orbits, and ocular hypertelorism.
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Pathophysiology

Craniosynostosis is an important cause of childhood morbidity. [8]  Crouzon syndrome arises from mutations in the fibroblast growth factor receptor-2 (FGFR2) gene. Crouzon syndrome with acanthosis nigricans (also called Crouzonodermoskeletal syndrome) has causal mutations in the FGFR3 gene. [9]

Sutures have a number of important functions, including provision of skull flexibility that allows changes in skull volume, thus accommodating brain growth in early life. They also maintain rigid connections between adjacent bones and, once central nervous system (CNS) growth is complete, provide for the alignment and fusion of adjacent bones. [8] Premature closure of cranial sutures results in craniofacial dysmorphology.

In the case of Crouzon syndrome, premature synostosis of the coronal, sagittal, and, occasionally, lambdoidal sutures begins in the first year of life and is completed by the second or third year. The order and rate of suture fusions determine the degree of deformity and disability. Once a suture becomes fused, growth perpendicular to that suture becomes restricted and the fused bones act as a single bony structure. Compensatory growth occurs at the remaining open calvarial sutures (parallel to the closed suture) to allow continued brain growth. Surgical intervention is required to alleviate raised intracranial pressure and to correct calvarial, facial, and dental deformations. [8]

Severe complex pansynostosis of all sutures leads to a so called cloverleaf skull, in which the brain protrudes through the open anterior and parietal fontanelles. As mentioned earlier, premature fusion of skull base sutures is often seen in cases of multiple sutural synostoses, with the resulting occurrence of midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, exophthalmos, maxillary hypoplasia, and occasional upper airway obstruction. [7, 10]

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Epidemiology

Birth prevalence

Craniosynostosis, in which one or more cranial sutures prematurely fuse, is a common malformation occurring in approximately 1 in 2000 live births. Of those, about 70-85% of cases are nonsyndromic. The rest consist of over 180 syndromes. [11]

Crouzon syndrome is now recognized as one of the most common craniosynostosis syndromes. [12] It accounts for approximately for 4.8% of all cases of craniosynostosis, with a birth prevalence 16.5 per million live births (1 in 60,000). [4] This figure may have been slightly overestimated, however, due to inclusion of cases of Muenke syndrome [12] and possibly also Saethre-Chotzen syndrome. Birth prevalence of 1 in 25,000 live births, from Cohen’s early paper, [3] is still often cited in the literature, but this figure most likely included other craniosynostosis cases and syndromes.

There are two explanations for the inconsistency of reported birth prevalence. First, the phenotypic features may not be present at birth and may instead develop gradually during the first year of life. [13] Second, even if there is a high or complete penetrance of a mutated allele, expressivity ranges widely, from very severe to mild. Very often, the mild forms are underascertained, as they may not lead an individual to seek a treatment. Mild forms may be diagnosed when relatives of patients with typical features of Crouzon syndrome are carefully examined.

Parental age

Glaser demonstrated strong evidence of a paternal age effect in the development of sporadic Crouzon syndrome, [14] although the association between older paternal age and sporadic mutations in Crouzon and Pfeiffer syndromes was described as early as 1975 by Jones and colleagues. [15] It has been suggested that the paternal age/Crouzon syndrome link may result from the accumulation of mutations in the germ line of older men or from the presence of a greater susceptibility to mutations in this age group. [14]

Sex

There is no sex predilection; males and females are equally represented among Crouzon cases.

Ethnicity

Individuals affected with Crouzon syndrome have been described in all ethnicities.

Morbidity

Morbidity in Crouzon syndrome depends on the severity of dysmorphology, symptoms, and treatment procedures, especially surgeries. The premature fusion of cranial sutures leads to facial and cranial dysmorphology, midface hypoplasia, shallow orbits, a foreshortened nasal dorsum, hypertelorism, ocular defects, and, occasionally, upper airway obstruction. Progressive hydrocephalus is common, occurring in about 30% of patients. [16] Crouzon syndrome has been associated with moderate cognitive impairment, [17, 18] but CNS abnormalities and high intracranial pressure are less frequent in Crouzon syndrome than in Apert syndrome. [19] There are no limb malformations involved in Crouzon syndrome.

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Prognosis

Early and correct diagnosis of Crouzon syndrome is critical for treatment planning and timing of every procedure. Prognosis depends on the severity of Crouzon syndrome. Care of a multidisciplinary team and case management in a craniofacial center is important. However, even very severe cases of Crouzon syndrome requiring several surgeries and challenging multidisciplinary treatment from infancy to adulthood can, eventually, present with excellent outcomes.

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Patient Education

Crouzon Support Network

A program of AmeriFace

PO Box 751112

Las Vegas, NV 89136

24-Hour Toll-free Hotline: (888) 486-1209

Phone:  (702) 769-9264, Fax: (702) 341-5351

http://www.crouzon.org/

info@ameriface.org

National Organization for Rare Disorders, Inc. (NORD)

55 Kenosia Ave

Danbury, CT  06810

Phone: 203-744-0100

Fax: 203-263-9938

https://rarediseases.org/rare-diseases/crouzon-syndrome/

March of Dimes

1550 Crystal Drive, Suite 1300

Arlington, VA  22202

Phone: 888-663-4637

FACES: The National Craniofacial Association

PO Box 11082

Chattanooga, TN 37401

Phone: (423) 266-1632

Toll-free: (800) 332-2373

Email: faces@faces-cranio.org

Cleft Palate Foundation

1504 East Franklin Street, Suite 102

Chapel Hill, NC 27514-2820

Phone: (919) 933-9044

Toll-free: (800) 242-5338

Fax: (919) 933-9604

Email: info@acpa-cpf.org

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