Crouzon Syndrome With Acanthosis Nigricans

A number sign (#) is used with this entry because of evidence that Crouzon syndrome with acanthosis nigricans (CAN) is caused by a specific heterozygous missense mutation in the FGFR3 gene (A391E; 134934.0011) on chromosome 4p16.

Description

Crouzon syndrome with acanthosis nigricans is considered to be a distinct disorder from classic Crouzon syndrome (123500), which is caused by mutation in the FGFR2 gene (176943). Cohen (1999) argued that this condition is separate from Crouzon syndrome for 2 main reasons: it is caused by a highly specific mutation of the FGFR3 gene, whereas multiple different FGFR2 mutations result in Crouzon syndrome, and the phenotypes are different.

Clinical Features

Breitbart et al. (1989) reported 6 patients with Crouzon syndrome and acanthosis nigricans and discussed the ramifications for the craniofacial surgeon. The authors noted that surgical sites within the areas affected by acanthosis nigricans often demonstrated marked hypopigmentation. Three of the 6 patients had choanal atresia.

Meyers et al. (1995) reported a mother and daughter with Crouzon craniosynostosis associated with acanthosis nigricans. Two additional patients had this combination without a family history. The patients had classic features of Crouzon syndrome without the typical skeletal manifestations of other disorders associated with FGFR3 mutations. The acanthosis nigricans was characterized by verrucous hyperplasia and hypertrophy of the skin with hyperpigmentation and accentuation of skin markings, especially in flexural areas. Although the association of acanthosis nigricans with certain congenital disorders had been recognized (Orlow, 1992), acanthosis nigricans associated with Crouzon syndrome was atypical in several ways: the onset was often early, apparent in childhood, and always by puberty; and the distribution included the axillae, neck, chest, abdomen, breasts, perioral and periorbital areas, and nasolabial folds. In addition, all 4 patients had multiple melanocytic nevi and choanal atresia, and 3 developed hydrocephalus. Meyers et al. (1995) noted that both choanal atresia and hydrocephalus are unusual findings in classic Crouzon syndrome. There was a female preponderance.

Wilkes et al. (1996) reported 3 unrelated patients with Crouzon syndrome and acanthosis nigricans. The first patient was a male who had proptosis and craniosynostosis since birth and developed dry skin and acanthosis nigricans at age 9 years. A female patient had feeding difficulties and failure to thrive associated with incomplete choanal atresia, midface hypoplasia, and bicoronal synostosis. The third patient was a 61-year-old man with abnormal skull shape with proptosis and hypertelorism. Radiographs showed brachycephaly and hypoplasia of the maxillary bones. Acanthosis nigricans was present since early childhood and progressed to generalized skin thickening and distribution of warty acanthomas over his back. Wilkes et al. (1996) emphasized the unusual distribution of the skin lesions, particularly in the perioral region.

Schweitzer et al. (2001) reported 3 cases of Crouzon syndrome with acanthosis nigricans and compared the clinical characteristics with 3 previously reported cases. All 6 patients had subtle radiographic findings of achondroplasia (ACH; 100800), including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Schweitzer et al. (2001) concluded that the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of Crouzon syndrome with acanthosis nigricans, even before the skin involvement appears.

Arnaud-Lopez et al. (2007) reported 2 patients with Crouzon syndrome and acanthosis nigricans. A 30-month-old girl had respiratory insufficiency, laryngomalacia, and craniosynostosis, and had developed acanthosis nigricans at age 21 months. Acanthosis nigricans occurred on the neck, flexion sites, nipples, abdomen, perioral and perialar regions. A CT scan at birth showed signs of increased intracranial pressure, choanal stenosis, and hypertrophy of turbinate bones. An unrelated girl had a cloverleaf skull at birth and hydrocephalus. She had normal development, proportionate short stature, craniosynostosis with crouzonoid characteristics, melanocytic nevi in the face and thorax, and limited extension of the elbows. Acanthosis nigricans, which was observed from the age of 4 years, affected periorbital, paranasal and perioral regions, the neck, thorax, abdomen, and flexion sites of the limbs. Hypopigmentation was evident in surgical scars of the neck and abdomen. Radiographic studies showed turribrachycephaly, hypoplastic malar bone, and fusiform distal phalanges. She also had a dysplastic right kidney, membranous glomerulonephritis, and terminal renal failure at age 14 years. Both patients had the FGFR3 A391E mutation.

In a review of 33 published cases of Crouzon syndrome with acanthosis nigricans, Arnaud-Lopez et al. (2007) found an increased female to male ratio of 2.4:1. Common features included craniofacial anomalies such as downslanting palpebral fissures, exophthalmos, ocular hypertelorism, midface hypoplasia, convex nose and posteriorly rotated ears. Most (80%) of patients developed acanthosis nigricans within the first decade, and its localization was widespread and atypical compared to acanthosis nigricans alone. Additional skin anomalies included hypopigmentation of surgical scars and melanocytic nevi. Choanal atresia was present in 41% and hydrocephalus in 43%. Some patients had oral abnormalities, including cleft palate, bifid and hypoplastic uvula, dental malocclusion, and cementomas of the jaw.

Other Features

Cohen (1999) noted that the FGFR3 A391E mutation is also associated with cementomas of the jaws, which is not found in classic Crouzon syndrome (Reddy et al., 1985; Superti-Furga et al., 1996). In addition, the interpediculate distances progressively narrow from the upper to the lower spine, as in achondroplasia (Superti-Furga et al., 1996), which is also caused by an FGFR3 mutation. Cohen (1999) suggested that radiographic studies of the jaws and vertebrae are indicated in cases of associated Crouzonoid phenotype and acanthosis nigricans.

Molecular Genetics

In 4 patients with Crouzon syndrome with acanthosis nigricans, Meyers et al. (1995) identified the same heterozygous A391E mutation (134934.0011) in the FGFR3 gene. This mutation was not present in 16 unrelated Crouzon syndrome patients with FGFR2 mutations, 13 unrelated Crouzon syndrome patients without FGFR2 IgIII domain mutations, or 50 unrelated controls. In addition, the authors found no FGFR3 mutations in 2 unrelated patients with isolated acanthosis nigricans (100600). In 1 kindred, a patient with Crouzon syndrome with acanthosis nigricans had a second cousin with classic Crouzon syndrome due to an FGFR2 mutation (S347C; 176943.0009), and the authors raised the possibility of a predisposing factor for FGFR mutations.

In 3 unrelated patients with Crouzon syndrome and acanthosis nigricans, Wilkes et al. (1996) identified the A391E mutation in the FGFR3 gene.

Nomenclature

Cohen (1999) urged that this disorder be called 'Crouzonodermoskeletal syndrome' for the Crouzonoid phenotype combined with the cutaneous and skeletal features, including jaw cementomas and vertebral alterations.