Peutz–Jeghers syndrome is inherited in an autosomal dominant pattern.

Mutations of STK11, a tumor suppressor gene on chromosome 19p13.3, are detectable in about 20–70 % of patients [6, 7].

Perioral pigmentation is pathognomonic, particularly if it occurs across the vermilion border. Oral mucosa and fingertips are also commonly affected. About 50 % of patients develop a wide variety of cancers in adulthood [10]. An overexpression of COX-2 has been reported in polyps and cancers related to PJS [11].

The majority of cases occur sporadically. Exceptional cases with autosomal dominant and recessive inheritance patterns have also been reported [17].

OAV represents a nonrandom cluster of development anomalies of the first and second branchial arch derivatives rather than a single gene defect [18]. Maternal diabetes may be etiologically significant [19].

Epibulbar dermoid is a necessary feature for the diagnosis of Goldenhar syndrome (Fig. 22.2). The epibulbar dermoids are almost always located near the limbus in the inferotemporal quadrants. Secondary irregular astigamstism and anisometropic amblyopia may also be present. Dermolipomas are typically in the subconjunctival plane and appear as a yellow soft mass in the superotemporal quadrant. Other associated anomalies include eyelid coloboma [20], Duane syndrome [21], and caruncular anomalies [22]. Involvement of the globe itself manifesting as microphthalmia and coloboma is uncommon [23].

In addition to ophthalmic, ear, and vertebral anomalies, about 50 % of cases have anomalies such as micrognathia, macrostomia, cleft lip and palate, and developmental defects of the heart [24]. Recent analysis of data suggests a statistical association with the VATER anomaly (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia) and CHARGE syndrome (coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies) [25].

Proteus syndrome is inherited in a sporadic fashion as it is due to mutations that are lethal unless they occur in a mosaic fashion [29]. It does not seem to recur in families, but does appear in disconcordant monozygotic twins, suggesting a somatic mutation that is lethal when constitutive [26].

Recent data [30] has refuted the role of germline PTEN mutation in causation of Proteus syndrome [31]. Newer studies have supported a role for the AKT1 c.49G → A variant in the cause of Proteus syndrome [26].

Ophthalmic involvement is common in Proteus syndrome. A review of more than 200 published cases revealed that more than 40 % of cases that met the diagnostic criteria had one or more ophthalmic features [32]. Epibulbar and eyelid dermoids, strabismus, nystagmus, high myopia, orbital exostoses, and posterior segment hamartoma are most commonly observed [33–35]. A complete list of published ophthalmic findings is given elsewhere [32–34].

The manifestations are usually present at birth and progress during childhood. Due to its varied manifestations, the diagnosis of Proteus syndrome is frequently missed. Critical review of published cases revealed that only 47 % of cases met the diagnostic criteria [32]. General features suggestive of this diagnosis include mosaic distribution of lesions, a progressive course, and sporadic occurrence [32]. Connective tissue nevi are pathognomonic. Other features include lipoma (92 %), vascular malformations (88 %), and epidermal nevi (67 %) (Fig. 22.3) [30]. The list of diagnostic criteria is reviewed elsewhere [36]. Individuals with significant clinical features but who do not meet the diagnostic criteria are labeled as having Proteus-like syndrome. The differential diagnosis of Proteus syndrome includes neurofibromatosis type 1, Klippel–Trenaunay–Weber syndrome, Maffucci’s syndrome, Ollier’s disease, and Bannayan–Ruvalcaba–Riley syndrome.

MEN 2B is inherited as an autosomal dominant trait. About half the cases are due to de novo mutations.

More than 95 % of patients with MEN 2B have a point mutation in the RET gene [39].

A comprehensive review of all published cases of MEN 2B reveals that common ophthalmic manifestations include prominent corneal nerves (100 %), eyelid neuroma or thickening (88 %), subconjunctival neuroma (79 %), and dry eyes (48 %) (Fig. 22.4) [40–42]. With rare exceptions [43], the presence of prominent corneal nerves in otherwise normal cornea should lead to investigations to exclude MEN 2B [40, 42]. Other infrequent causes of prominent corneal nerves such as neurofibromatosis, leprosy, and congenital ichthyosis should also be considered in the differential diagnosis [42]. Histopathologic findings of the cornea have shown that prominent corneal nerves are axonal bundles of nonmyelinated nerves in association with Schwann cells [44, 45].

A clinical diagnosis of MEN 2B is suspected in the presence of a marfanoid body habitus, mucosal neuromas of the lips and tongue, prominent corneal nerves, and medullary thyroid carcinoma [38]. As medullary thyroid carcinoma tends to be aggressive, early prophylactic thyroidectomy is recommended [46]. Patients may also have chronic constipation and colonic cramping due to megacolon disorder [47]. About half of patients with MEN 2B also develop pheochromocytoma. Unlike other types of MEN, involvement of the parathyroid gland is rare in MEN 2B [48].

Xeroderma pigmentosum is inherited as an autosomal recessive trait with full penetrance [49, 50]. Therefore, the possibility of consanguinity should be explored.

Xeroderma pigmentosum is due to mutations of one of eight genes that are involved in nucleotide excision repair [51–53]. The products of seven of these genes (XP–A through G) are involved in nucleotide excision repair of DNA damaged by UV light [50]. The eighth gene (POLH) codes for a special polymerase used to replicate damaged DNA [50]. Cockayne syndrome and trichothiodystrophy, two related disorders of defective nucleotide excision repair mechanisms [54], unlike xeroderma pigmentosum, are not associated with the risk of developing skin cancers [55].