Blau syndrome (BS) (OMIM # 186580), also known as familial juvenile systemic granulomatosis , is a rare autosomal dominant systemic granulomatous disorder caused by a mutation in the NOD2 gene. Blau syndrome usually presents before age 4 [4]. The classic triad of Blau syndrome was uveitis, arthritis, and exanthema.

Blau syndrome was initially described in 1985 by Dr. Blau and Dr. Jabs, who both reported families with granulomatous disease of the eyes and joints and were HLA B27 negative. Since then, many further reports were published that expanded the phenotypic variations to include fever, cranial neuropathies, cardiovascular abnormalities and visceral granulomas, including the liver and kidneys [4]. In 2009, an international registry was merged, and contains more than 100 cases of BS. There have been fewer than 200 persons belonging to 63 families with BS reported in the literature.

Skin inflammation usually presents as a granulomatous dermatitis as early as 1 month of age with tiny red/tan dots that start on the face and spread to the trunk. This rash consists of discrete erythematous plaques with multiple papules. The rash can be scaly or have hard nodules under the skin. Arthritis is usually a polyarticular synovitis and tenosynovitis and is commonly present (95 %). Camptodactyly with synovial cysts are also be present. Other systemic findings, such as cardiovascular, visceral and cranial nerve abnormalities, are present in approximately one-third of patients with BS [4].

Diagnosis can be made by clinical findings, family history, genetic analysis, and biopsy of skin lesions or joint fluid revealing noncaseating granulomas. Clinically, BS may be indistinguishable with early-onset sarcoidosis (EOS) as both entities involve inflammation of skin, joints, and eyes. Both disorders are also caused by mutations in the NOD2 gene, but the main difference is in the inheritance pattern where BS has an autosomal dominant inheritance pattern and EOS usually arises from de-novo mutations [4].

The most common ocular finding is granulomatous uveitis, which usually occurs in the first decade [5]. It is never the presenting symptom of BS but carries the greatest morbidity for patients with BS. It is what often drives the need for treatment [4]. Uveitis is can be in the form of bilateral anterior uveitis, vitritis, panuveitis, and/or multifocal choroiditis. Macular edema, optic nerve edema, and retinal detachments are also known to occur as well as other complications including band keratopathy, cataracts, and glaucoma. Significant visual loss has been reported in up to 46 % of patients [4].

Children with uveitis due to BS are treated similiarly to those with juvenile idiopathic arthritis [4]. Systemic treatment includes low to moderate steroids or methotrexate, with variable success. TNF-α (tumor necrosis factor-alpha) inhibition has also shown some efficacy in recent years [6]. There have been some reports of success with thalidomide and IL-1 receptor antagonists in small case series.

Blue rubber bleb nevus syndrome (BRBNS) (OMIM #112200) is a venous vascular malformation syndrome primarily involving the skin and the gastrointestinal tract [7, 8]. BRBNS was initially described by Gascoyen in 1860, who reported the association of vascular hamartomas of the skin with intestinal lesions and gastrointestinal bleeding. Bean coined the term “blue rubber bleb nevus syndrome” in 1958 and since then, the disorder has been also termed Bean’s syndrome. To date, fewer than 150 cases of BRBNS have been reported in the literature. Cases of autosomal dominant inheritance have been described, but most are sporadic [7].

Bluish venous malformations in BRBNS have a range of clinical appearance from small blue-black punctate papules to large disfiguring tumors. The most characteristic cutaneous lesion is raised, nipple like and refills slowly after compression. They can be numerous, numbering up to several hundred and most often occur on trunk or extremities. While many lesions are present at or shortly after birth, some have been diagnosed prenatally as early as in the fifth month of gestation. Lesions can increase in size and number with age [8]. In the past, these lesions have been incorrectly categorized as hemangiomas but now recognized as venous malformations. They have been occasionally reported on the face and eye [9]. Although many can by asymptomatic, pain and hyperhidrosis may be present. Skin lesions do not bleed spontaneously or undergo malignant change [8].

Gastrointestinal venous malformations are most often in the small intestines but can be present anywhere from the mouth to the anus . These lesions can result in frequent bleeding, potentially leading to occult blood loss and iron-deficiency anemia. Abdominal pain and other complications including intussusception, volvulus and infarction have been described. Venous malformations have been described in other organs including adrenal glands, kidneys, heart, lungs, bladder, penis, thyroid, spleen, central nervous system and muscle [8].

BRBNS is diagnosed clinically based on classic cutaneous findings. Basic evaluation should consist of complete history, physical exam, blood count and stool guaiac test. Histologically, vascular lesions are characterized by clusters of dilated irregular capillary spaces lined by a thin layer of endothelial cells in the dermis or subcutaneous fat [8]. Early diagnosis is important as gastrointestinal tract lesions can cause life-threatening hemorrhage, consumptive coagulopathy and iron-deficiency anemia [7].

Ocular findings included vascular lesions in the conjunctiva, iris, and macula. Orbital lesions have been reported as well, which have presented with sudden proptosis or intermittent proptosis with increase in intrathoracic pressure [7]. They are often tender with localized hyperhydrosis. Orbital lesions can be complicated by occurrence of thrombosis [7].

Treatment for cutaneous lesions is required only when lesions are cosmetically disfiguring or functionally bothersome. Treatment modalities include Ruby, argon, and carbon-dioxide laser treatments, electrodessication, surgical excision and injection sclerotherapy. Pulsed dye laser is the most successful treatment for removing hundreds of lesions without recurrences [8].

Symptomatic gastrointestinal lesions can be treated with endoscopic photocoagulation, laser, sclerotherapy, or surgical excision. Oral iron supplementation is crucial in treating associated anemia with occult blood loss [8, 10].

Cowden syndrome (OMIM #158350) is an autosomal dominant cancer syndrome with increased risk for benign and malignant neoplasias [11]. It was initially described in 1962 as a mainly dermatologic disease; however, over time, the phenotypic spectrum has expanded to include cancer risks and neurodevelopmental disorders. The defect is associated with mutations in the tumor suppressor gene protein tyrosine phosphatase and tensin homologue (PTEN) . It is now recognized that Cowden syndrome is part of a larger syndrome called PTEN hamartomatous syndrome , which includes Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome. These conditions all have risks of developing specific cancers. These syndromes are still considered to be heterogeneous as PTEN mutation may not be detected in all cases. Prevalence of PTEN mutation in Cowden syndrome is 80 % and 60 % in Bannayan-Riley-Ruvalcaba [12].

Cowden syndrome usually presents in the second or third decade of life. Mucocutaneous features include numerous flesh colored benign hamartomas coalescing in the skin to give a cobblestone appearance. Other dermatologic findings include lipomas, fibromas, and freckling of the glans penis. Tumors occur throughout the body in all three germ cell layers, with predilection for the breast, thyroid, endometrium, skin, and gastrointestinal tract [12]. In addition, high-flow vascular malformations accompanied by increased adipose tissue are frequently found in PTEN hamartomatous tumor syndromes. Among the first 100 cases of Cowden syndrome, the most common manifestations were thyroid goiter (68 %), fibrocystic breast disease (52 %), GI polyps (35 %), lipomas (31 %), and macrocephaly (21 %). Estimated breast cancer risk of 25–50 % is reported. A slight increase in risk for melanoma (6 % compared to 2 % in general population) is reported in patients with PTEN mutations. Annual dermatologic examination is recommended. Lhermitte-Duclos disease , or dysplastic gangliocytoma of the cerebellum, is a phenotypic variant of Cowden syndrome. Severe forms can be life-threatening with increased intracranial pressure, ataxia, and seizures.

Bannayan-Riley-Ruvalcaba syndrome (BRRS, OMIM # 153480) is the name used to denote the combination of three conditions formerly recognized as separate disorders which are Bannayan-Zonana, Riley-Smith, or Ruvalcaba-Myhre-Smith syndromes . It is an autosomal dominant syndrome of pediatric onset characterized by macrocephaly, hamartomas, hemangiomas, penile lentigines, and developmental delay [12]. Ophthalmic findings include downward slanting palpebral fissures, hypertelorism, strabismus, and pseudopapilledema [12].

Several characteristics as listed below should raise strong clinical suspicion for PTEN hamartomatous syndrome [11]:

Trichilemmomas are tumors of the outer root sheath follicular epithelium that occur in isolation or in association with Cowden syndrome. Individual lesions measure between 3 and 8 mm in diameter and are generally smooth surfaced but a pileup of keratin can simulate a cutaneous horn [13]. Papillomatous papules also occur around the eyes and face. Retinal hamartomas can also be present, potentially leading to vision loss [14]. Retinal neovascularization in patients with Cowden syndrome has been described and is thought to be due to PTEN’s role in regulating VEGF-regulated angiogenesis [15].

Most critical aspect of management of patients with Cowden syndrome is heightened cancer surveillance according to the screening guideline advocated by National Comprehensive Cancer Network (NCCN) [12].

Local excision of trichilemmomas are often adequate with careful scrutiny of surgical margins to prevent benign recurrence [13].

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome with increased risk for squamous cell carcinoma and hematolymphoid neoplasms [16]. First described by Zinsser in 1906, it is a disease of telomere maintenance dysfunction and can be inherited in autosomal dominant, autosomal recessive and X-linked recessive patterns [16]. Telomere maintenance has a significant role in aging and cancer predisposition. DC patient have premature telomere shortening, ultimately leading to premature stem cell exhaustion and tissue failure. Estimated annual incidence is <1 in one million. DC occurs more commonly in males, and clinical signs manifest around ages five to twelve [16].

The classic triad of dyskeratosis congenita is nail dystrophy, mucosal leukoplakia, and lacy reticular hyperpigmentation and atrophy of the upper body. It may be commonly accompanied by alopecia and premature graying as well. Skin and nail changes first appear. Nail dystrophy (present in 90 %) begins with ridging and longitudinal splitting and progresses to result in rudimentary or absent nails. Mucosal leukoplakia (80 %) can occur in the buccal mucosa, oropharynx, and tongue, and about 30 % of these leukoplakic areas can develop into squamous cell carcinoma, requiring frequent monitoring [16]. Other manifestations include dental, gastrointestinal, skeletal, neurological, immunological, ophthalmic, genitourinary and pulmonary tissue involvement. Additional minor features of dyskeratosis congenital are as follows: microcephaly, developmental delay, excessive sweating, short stature, hypogonadism, liver disease, and osteoporosis [16]. The most common complication of dyskeratosis congenita is bone marrow failure in childhood and pulmonary fibrosis in adults [16]. Bone marrow failure occurs in 80–90 % of cases by age 30 years and is the leading cause of death in patients with DC .

Eye problems develop in approximately 40–50 %. Most common findings are nasal lacrimal duct obstruction, trichiaisis, and cicatricial entropion, likely secondary to epithelial abnormalities in ocular skin and mucous membranes. Complications can lead to recurrent blepharitis, conjunctivitis, keratitis and permanent corneal changes. Retinal abnormalities can also occur and include hemorrhages, granular retinal pigment epithelium changes, peripheral retinal nonperfusion and retinal neovascularization [16, 17]. Exudative retinopathy has been reported to be specific to Revesz syndrome, a severe variant of DC . In addition to the syndrome specific ophthalmic findings, patients who receive radiation and steroids as treatment can develop cataracts, glaucoma and radiation retinopathy and optic atrophy [17]. Ophthalmologic evaluation should be performed on every patient with DC on diagnosis, and subsequent examinations should be part of their routine care.

The only curative treatment is allogenic hematopoietic stem cell transplant. Bone marrow failure with DC does not respond will to immunosuppressive therapy. About 50–70 % of DC patients respond to androgens. These patients should be monitored closely for abnormalities in lipid profile and liver function [16].

Epidermolysis bullosa (EB) is a group of disorders characterized by fragile epithelial tissue that is prone to blistering even with minor trauma [18]. EB is inherited as either autosomal dominant or autosomal recessive disease, depending on the type and subtype. Mutations in at least 18 genes have been identified to cause EB. These genes express various signaling and structural proteins within the epidermis and at the epidermal-dermal junction [19]. EB is classified under four major types: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler syndrome. Each of these forms has many different subtypes.

EBS is the term for EB with blistering confined to the epidermis. It can be subdivided based on whether the blisters occur in the suprabasal or basal layer [19, 20]. Intraepithelial blisters come from cytolysis of the basal cells. Onset of disease usually occurs at or shortly after birth. Patients with milder forms of localized EBS may not develop symptoms until late childhood or early adulthood [19]. Depending on the subtype, patients can have varying severity of milia, scarring and nail dystrophy, especially when compared to the other forms of EB [19].

In JEB, blisters develop in the junction, also called the lamina lucida, of the skin basement membrane zone. One characteristic clinical finding of JEB is the presence of enamel hypoplasia, which presents as localized or generalized pitting of tooth surfaces [19]. JEB-Herlitz is the more severe subtype that comprises about 20 % of the American JEB population. Extensive granulation tissue formation that arises in within the first few months to 2 years of life is pathognomonic finding of JEB-Herlitz [19]. Hands and feet are relatively spared, but mucosal membrane involvement can be severe, leading to complications such as tracheolaryngeal obstruction and esophageal strictures [19]. Growth retardation and multifactorial anemia is almost always present [19]. Severe ocular problems can occur including corneal erosions, scarring and ectropion formation [19]. Bacteremia , septicemia and death usually occurs before 3 years of age. Non-Herlitz, JEB is more common but has less severe symptoms and complications. Prominent features include hypopigmentation of skin, atrophic scarring and alopecia [19].

DEB can be subcategorized into autosomal dominant and autosomal recessive types. In both forms, blisters are located within the uppermost dermis, also known as the sub-lamina densa layer of the basement membrane zone [19, 20]. In general, all have some degree of blistering that in severe cases can cause of fusion of skin around digits, and scarring of the skin. Dystrophic or absent nails are common. Recurrent esophageal blistering leading to stricture is also common in both dominant dystrophic EB (DDEB) and recessive dystrophic EB (RDEB) . DDEB tends to present with a mild phenotype. Blisering in the newborn period is common, but this tendency may decrease with age [21]. Patients with RDEB tend to have extensive blistering and erosions that develop from birth. The extensive and recurrent blistering and scarring often leads to pseudosyndactyly, or loss of interdigital space and contractures [21]. RDEB patients are at a higher risk for developing metastatic squamous cell carcinoma [19].

Kindler syndrome is a rare, autosomal recessive form of EB, which was added to the EB classification in 2008. It represents EB with blistering that occurs in multiple levels of the skin, rather than in a specific plane as in the other types of EB [20]. Clinical manifestation occurs at birth as generalized blistering and later as characteristic poikilodermatous pigmentation, skin atrophy, and photosensitivity [19]. Teeth are not involved although gingival fragility can be seen.

Diagnosis of EB can be made by the collective findings acquired from personal and family history and with laboratory data including immunofluorescence antigenic mapping and transmission electron microscopy [19]. Genetic testing for the specific mutations causing EB in a patient is often preferred because it can be helpful to distinguish cases in which clinical findings alone are unclear and help guide genetic counseling and future management and treatment.

Eye involvement can occur in all types of inherited EB as ocular surface is derived from ectoderm like the skin (Figs. 8.1, 8.2, 8.3). Common ocular signs of EB include conjunctival irritation, corneal erosions, exposure keratopathy, and cicatrisation of eyelids and conjunctiva [22]. Corneal blister formation, either as intact vesicles or corneal erosions is one of the most common findings in EB [18]. Corneal findings have been reported in about 50–60 % of patients with JEB and RDEB as opposed to 1–6 % in EBS patients [18]. Repeated episodes can lead to pannus formation and corneal scarring. Symblepharon formation is confined to JEB and RDEB. Lacrimal duct obstruction has been reported in all EB types but in highest frequency in RDEB (12 %). Ectropion formation most often occurs in JEB patients (14 %). Patients with minimal symptoms, especially those with EBS, do not need regular eye exams as long as the patient and parents are cognizant of the symptoms and importance for evaluation when symptoms arise [22, 23]. For patients with JEB and RDEB , at least a biannual ophthalmic exam is recommended given the morbidity associated with the increased risk for ocular complications [22].

The main therapy for ocular involvement is maintaining moisture and lubrication for irritated ocular surfaces from dryness and poor eyelid function [22]. In case of corneal erosions, soft contact lenses and topical antibiotic may be helpful under close monitoring. Ocular surface reconstruction and eyelid surgeries may be required for severe ocular involvement.

There is no effective cure for EB at present although active research promoted in the areas of gene therapy and cell therapy [24]. Prognosis is highly dependent on the type or subtype of EB. Patients with EBS and DDEB have normal life expectancy although with significant morbidity due to complications that can occur. Supportive care to prevent scarring, strictures and infection is crucial. Some forms of EB require daily wound dressing changes, which may take several hours to perform. Surgical intervention may be useful to prevent permanent deformities, and laser, skin grafts, tissue-engineered skin grafts, amniotic membranes, have been tried with variable success. GI strictures of oropharynx can often be problematic and endoscopic dilation has been employed. Bone-marrow transplant and gene-based therapies are in evolution .

Goltz Syndrome or focal dermal hypoplasia (FDH) (OMIM#305600) is a rare, X-linked dominant disorder of congenital mesodermal and ectodermal abnormality [25]. About 250 patients have been reported, mostly in females although there are few (usually mosaic) males affected with FDH. About 95 % of cases occur sporadically and 5 % are familial [25, 26]. It is due a mutation in PORCN gene , which is involved in the secretion and signaling of Wnt proteins that play a role in embryonic tissue development [25].

FDH is a multisystem disorder primarily involving the skin, skeletal system, eyes, and face. Classic features are patchy, hypoplastic skin, split hand/foot deformities, and ocular abnormalities [25]. In FDH, cutaneous findings are variable and can be present at birth or develop with age. Most characteristic feature is the blistering and widespread hypoplasia or aplasia of the skin that frequently follows Blashko’s lines, which are the cell migration pathways that are linear on the limbs and circumferential on the trunk [27]. Hypoplastic areas are usually evident at birth although the severity and distribution may change with time. Unilateral involvement has also been reported [28]. Numerous soft tan papillomas may develop with age. Verrucoid papillomas commonly occur around the mouth and nose but also can be present in the esophagus, larynx and in genitoanal region [27]. Dystrophic or hypoplastic nails are less common. Sparse and brittle hair, and localized areas of alopecia are present. There can also be absent or supernumerary nipples [27].

Most patients with FDH have limb malformations evident at birth, including, syndactyly, oligodactyly, and split-hand/foot malformation [25, 27]. Less common malformations include camptodactyly and reduction defects of long bones. Osteopathia striata , which is a striated appearance of bones on X-rays, is commonly seen. Costovertebral segmentation abnormalities, such as fused ribs and hemivertebrae, are present at birth. These malformations may cause scoliosis as the child grows. Fibrous dysplasia of bone may affect any bone at any time. They are often asymptomatic but becomes evident when it is the site of a pathologic fracture. Giant cell-like tumors of long bones have been reported in associated with FDH and may develop in childhood or adulthood [27].

Craniofacial abnormalities include facial asymmetry, notched alae nasi, pointed chin, and small underfolded pinnae. These characteristics usually develop with time. Oral manifestations, including enamel hypoplasia, hypodontia, sypernumerary teeth, microdontia, taurondontia (prism-shaped molars), and fused teeth, are seen in more than half of affected individuals. Abnormalities of gastrointestinal and urogenital systems also occur such as diaphragmatic or fat herniations and structural abnormalities of kidneys [25, 27]. Development is usually normal for individuals with FDH. Some may have cognitive impairment [27].

Following evaluations are recommended to establish of extent of disease in individuals diagnosed with FDH: Chest X-ray , eye exam, consideration of abdominal MRI, renal ultrasound, hearing evaluation, and medical genetics consultation [27].

Ocular abnormalities occur in 40 % of FDH cases [29] (Fig. 8.4). The most frequent manifestations are ocular colobomas, strabismus, and microphthalmia [28]. Anophthalmia, hypertelorism, nasolacrimal duct obstruction, and lid abnormalities such as ectropion and ptosis may occur in patients with FDH. Anterior segment problems include aniridia, heterochromia, subepithelial corneal opacities, corneal clouding and blue sclera. In addition to retinal colobomas, other posterior abnormalities such as optic nerve atrophy, retinal neovascularization and vitreous hemorrhages have been reported as well [30, 31].

Patients with significant dermal aplasia require regular care with a dermatologist with use of occlusive dressings and antibiotics creams to prevent secondary infections [27]. Pulsed dye laser may be helpful in some cases. Verrucoid papillomas may require surgical or laser therapy if they are present in the GI tract and causes obstruction or dysphagia [27]. Management of ocular abnormalities depends on the extent and severity of the symptoms.

The ichthyoses are a group of disorders with abnormal epidermal differentiation characterized by variable presentation of scaling and hyperkeratosis [41]. The Greek root, ichthys, means fish, referring to the scaling that resembles scales of a fish [42]. Patients with ichthyosis have compromised barrier function of the skin and therefore, have increased susceptibility to infection, dehydration, and chemical or mechanical assault [42]. Ocular manifestations are present with variable severity in ichthyosis and includes blepharitis, lagophthalmos, madarosis, ectropion, and risk of corneal damage [43] (Fig. 8.5). Peripheral fundus pigmentation and corneal opacities have also been reported in the literature [44]. Reversible conduction deafness can also occur in all types due to desquamation within the external auditory canal [43]. Ichthyoses can be divided into several categories as follows: Ichythyosis vulgaris, autosomal recessive congenital ichthyosis, X-linked ichthyosis , keratinopathic ichthyosis. Ichthyosis is considered nonsyndromic when only skin findings are present and syndromic when other organs are involved [43, 45].

Ichthyosis vulgaris (OMIM 146700), also known as ichthyosis simplex, is a nonsyndromic ichthyosis caused by homozygous or heterozygous loss-of-function mutations in the filaggrin (FLG) gene on chromosome 1q21 [46]. It is the most common type with prevalence of 1:100 [41]. Clinical onset occurs within the first year of life. It is characterized by scaling, xerosis, keratosis pilaris, palmar and plantar hyperlinearity (deeper furrows), and a strong association with atopic disorders [46]. Scales can be fine (powdery) or coarse (polygonal) and involve the extensor surfaces of limb, trunk and face [46]. Ocular manifestation is limited to mild scaling of the eyelids. There is spontaneous improvement of symptoms during summer [41].

Autosomal recessive congenital ichthyosis (ARCI) is a group of nonsyndromic ichthyosis without a tendency toward blistering. ARCI includes lamellar ichthyosis (LI) , congenital ichthyosis erythroderma (CIE) , harlequin ichthyosis (HI) and less commonly, self-healing collodion baby, acral self-healing collodion baby, and bathing suit ichthyosis [41, 42, 45]. Patients with ARCI are usually born prematurely, enveloped in a shiny, taut, cellophane-like collodion membrane [42]. The tight skin around the eyes and mouth can cause ectropion and eclabium, eversion of lips. Collodion babies look very similar at birth, but as the membrane dissolves in the first weeks of life, they take different clinical courses. In about 10 %, the skin findings resolve spontaneously as the membrane disappears [41]. This benign course is referred to as self-healing collodion baby. The most severe and often fatal type of ARCI is harlequin ichthyosis (OMIM 242500), which is caused by mutations in the ABCA12 gene (2q35) [42]. The membrane that encase neonates with HI are thick and armor-like, resembling harlequins and hence the name. When patients with HI survive the neonatal period, they have the phenotype of severe CIE. LI and CIE are very similar except that LI lack the presence of erythroderma. LI (OMIM 242300) is most commonly due to mutations in the keratinocyte transglutaminase (TGM1) (14q11.2). CIE is due to mutations in several genes, including TGM1 and ALOX12B [45]. The most common ocular abnormality seen in ARCI is cicatrical ectropion of the upper and lower lids [47]. This occurs from progressive subepithelial cicatrization and abnormal cornification of eyelid skin that leads to lagophthalmos, corneal exposure and keratopathy [48, 49]. Severe ectropion requires full-thickness skin grafts. Penile skin graft has been used successfully as it does not seem to be affected by the disease. When autograft is not possible, options include allograft overlay, mucous membrane, human engineered skin, and maternal skin allograft [48, 49]. Ophthalmologic evaluation upon diagnosis and close follow up to assess corneal integrity is recommended.

X-linked ichthyosis (OMIM 308100), also known as steroid sulfatase deficiency , is an X-linked recessive disorder due to a complete deletion or an inactivating mutation of the STS gene [42]. Its prevalence is 1:4000 [41]. Because steroid sulfatase is also deficient in the placenta, there is low maternal urinary estrogen secretion and low amniotic fluid estrogen , leading to difficult labor [42]. Affected males have pink or red skin with large translucent scales at birth. X-linked ichthyosis is associated with cryptorchidism (~20 %), attention deficit hyperactivity syndrome (40 %), and autism (25 %) [41]. White, comma-shaped corneal opacities in descemet membrane are present in 10–50 % of patients. These opacities do not affect vision but can cause recurrent corneal erosions and scars. Up to 25 % of female carriers also have these corneal opacities.

Keratinopathic ichthyosis refers to ichthyosis due to mutations in keratin genes (KRT) where blistering of skin is a prominent feature. It includes epidermolytic ichthyosis, superficial epidermolytic ichthyosis and congenital reticular ichthyosiform erythroderma. Inheritance is usually autosomal dominant although autosomal recessive forms can occur [41].

Few of the important syndromic ichthyoses are Refsum disease, Sjogren-Larsson syndrome (SLS) , keratitis-ichthyosis-deafness syndrome (KID) , ichthyosis follicularis alopecia and photophobia (IFAP) , and X-linked chondrodysplasia punctate 2 [3]. Individuals with Refsum disease and Sjogren-Larsson syndrome often have retinopathy. In SLS, macular crystalline inclusions, “glistening dots,” appear in infancy and increase with age [50]. Symptoms are variable in severity and seem to stabilize in late childhood. In addition to maculopathy, SJS patients have spastic paraplegia, intellectual disability, and ichthyosis. Individuals with KID have vascularizing keratitis (95 %). Although the word keratitis suggests a primary inflammatory disease, corneal abnormalities in KID results from generalized ectodermal disturbance with lid disease and limbal stem cell deficiency. Surgical treatment for corneal disease including limbal allografts, corneal grafts, lamellar keratoplasty, and amniotic membrane transplantation have been reported to be unsuccessful in patients with KID [51]. IFAP is characterized by the triad of ichthyosis follicularis, alopecia and photophobia. Photophobia is an essential feature for diagnosis and can present early in life or later in childhood. Corneal ulceration and vascularization often progress to scarring and vision loss [52]. Individuals with X-linked chondrodysplasia punctate 2 have growth deficiency, distinctive craniofacial appearance, ichthyosis and ocular changes. Congenital cataracts are present in 67 % of patients and can be asymmetric or sectoral. Microphthalmia and microcornea have also been reported.

Treatment for ichthyoses is mostly symptomatic and supportive. The goal is to reduce scaling and providing a humidified, temperature -controlled environment. Urea-based ointments, glycerin-based ointments, and lactic acid-based ointments are available [41]. Vitamin A ointments may be used for problem areas. When necessary, systemic retinoids can be administered with caution, being mindful of the potential teratogenicity and risk for increased intracranial pressure. In certain types such as KID , it may worsen ocular surface disease [53]. Daily baths with only water or mild soap is crucial as well. Lubrication for eyes and eyelids is warranted for those at risk of exposure keratopathy. As mentioned previously, severe ectropion may require surgical correction. For TGM1-associated ichthyosis, a causal topical enzyme replacement therapy is on the horizon [41].

Kinky hair disease, also known as Menkes disease , is a X-linked recessive disorder of copper transport and metabolism [54, 55]. It is cause by mutations in the copper-transporting ATPase gene (ATP7A) . Impaired intestinal copper absorption leads to reduced the activities of copper-dependent enzymes are decreased, ultimately resulting in inhibited formation of collagen, elastin, keratin, ceruloplasmin, and melanin. The clinical spectrum of ATP7A-related copper transport disorders ranges from the most severe form in classic Menkes disease to the less severe forms in occipital horn syndrome and distal motor neuropathy [55]. Incidence of Menkes disease is 1 in 100,000 to 250,000 live birth [54, 55].

Infants with classic Menkes disease appear healthy until age 2–3 months when they develop hypotonia, failure to thrive, seizures and neurodegeneration [55]. Then, hair changes become manifest. Scalp and eyebrow hair are short, sparse, twisted, and often lightly pigmented. They can be reminiscent of steel wool cleaning pads. Light microscopy reveals pili torti (hair shafts twisting 180°), trichoclasis (transverse fracture of the hair shaft), and trichoptilosis (longitudinal splitting of the hair shaft). Other clinical features of Menkes disease include distinctive facial features (jowly appearance with sagging cheeks), pectus excavatum, skin laxity especially on the nape of the neck and trunk, umbilical or inguinal herniae, vascular tortuosity, and bladder diverticulae [55]. Subdural hematomas and cerebrovascular accidents are common. Electroencephalograms are moderately to severely abnormal including high rates of status epilepticus and infantile spasms. Diagnosis is usually made around 8 months of age. Biochemical testing reveals low levels of copper in plasma, liver and brain due to impaired intestinal absorption, reduced activities of copper-dependent enzymes, and paradoxical accumulation of copper in certain tissues (duodenum, kidney, spleen, pancreas, skeletal muscle, placenta) . Early treatment with parenteral copper is crucial. Sometimes, even with early treatment, infants with classic Menkes disease progress to severe neurodegeneration and death between ages 7 month to 3 years. The most common cause of death is respiratory failure, often due to pneumonia [55].

Infants with mild Menkes disease have better motor and cognitive development compared to those with classic Menkes disease . They may talk and walk independently but have characteristic neurologic features of weakness, ataxia, head bobbing. Seizures, if present, manifest in mid-late childhood. Pili torti are present. Connective tissue and skin problems may be more prominent than in classic Menkes disease [55].

There is high prevalence of very poor visual acuity in patients with Menkes disease [54, 56]. Poor vision is attributed, in part, to acquired, progressive ganglion cell atrophy that leads to macular and optic nerve atrophy. Optic discs pallor is commonly seen in younger patients and become paler as they age [54]. Vision changes also occur due to retinopathy, which is caused by overall systemic copper deficiency and the loss of retinal Menkes protein that regulates copper levels in photoreceptors [57]. Retinal vascular tortuosity with mild retinal hemorrhages may rarely occur abnormal electroretinographic findings have been reported in patients with Menkes disease [56].

Myopia and strabismus also occur at a high rate. Patients may also have rotary nystagmus and gaze-evoked nystagmus, especially with anticonvulsant therapy. Other findings include blue irides, iris stromal hypoplasia, aberrant lashes, and peripheral retinal hypopigmentation [54, 56]. These features can also be present in mild variants of Menkes disease. The high prevalence of poor vision, refractive error, and strabismus warrants early eye exam for individuals diagnosed with Menkes disease .

To date, there is no curative treatment for Menkes disease. Early copper replacement therapy has been shown to improve neurologic outcomes [58]. Benefit increase when treatment begins prior to appearance of signs of symptoms. Early diagnosis based on positive family history and high index of suspicion is crucial in order for early treatment initiation [55, 58]. After diagnosis, patients with Menkes disease should undergo developmental assessment, evaluation of feeding and nutrition and assessment of bladder function in order to establish the extent of disease. Some patients may need gastrotomy tube placement to manage caloric intake or surgery for bladder diverticulae , if present [55].

Cardiofaciocutaneous (CFC) syndrome is an autosomal dominant multiple congenital anomaly disorder. It is one of the RASopathies , which are disorders caused by mutations in the Ras/MAPK pathway [59, 60]. Other syndromes in this group include Noonan syndrome and Costello syndrome. CFC was first reported in 1986 with major features of craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth delay, and intellectual disability.

Virtually all CFC patients develop cutaneous findings. These dermatologic manifestations help differentiate CFC from other RASopathies [60]. Numerous acquired melanocytic nevi and keratosis pilaris (follicular hyperkeratosis of extremities and/or face) is seen in majority of patients with CFC. Abnormalities in hair are common and includes curly scalp hair, sparse hair at the temples, poor hair growth, sparse arm and leg hair. Ulerythema ophryogenes , which is brow erythema with loss of follicles, leads to sparse or absent eyebrows in 90 % of individuals with CFC [60]. Abnormal sweating often leads to heat intolerance and axillary body odor. Other dermatologic findings include eczema, dystrophic nails with rapid nail growth, acanthosis nigricans, and generalized hyperpigmentation. Infantile hemangiomas are more commonly seen in CFC individuals (25 %) compared to other RASopathies and general population. In adolescence and adulthood, individuals may develop palmo-plantar calluses and peripheral lymphedema, often in the lower limbs [60].

Neurologic abnormalities are also universally present and can range in severity. Hypotonia, motor delay and learning disabilities are common. Examination may reveal macrocephaly, corticospinal tract findings, touch sensitivity, and tactile defensiveness. These findings are often accompanied by structual malformations on brain imaging. Seizures are present in 40–50 % of children with CFC [61, 62].

Failure to thrive and poor growth in infancy due to severe feeding problems are seen is almost all individuals with CFC. Swallowing difficulties can be detected early by prenatal polyhydramnios that is followed by difficult maintaining adequate oral intake after birth. Oral aversion and sensory integration difficulties with solid foods can continue through adulthood. Short stature is common in all RASopathies , including CFC [59, 60].

Nearly 75 % of individuals with CFC have cardiovascular involvement, ranging from congenital pulmonic stenosis (most common) and heart valve anomalies to progressive hypertrophic cardiomyopathy (40 %). Other systemic findings include scoliosis (33 %), pes planus (66 %), hyperextensibility of joints, renal/urogenital abnormalities (33 %), laryngotracheal abnormalities, and abnormal ear canals necessitating ear tube placements [59, 60].

Most individuals with CFC have ocular manifestations. Most commonly seen are strabismus , refractive errors, nystagmus, ptosis, and optic nerve hypoplasia. Exotropia is the most common type of strabismus encountered, and most require surgical correction in early infancy/childhood . Amblyopia is a common finding and must be treated early. Optic nerve changes ranges in severity. Craniofacial features include ocular hypertelorism, epicanthal folds, and hypoplastic supraorbital ridges. Most ocular problems in CFC are amenable to treatment. Thus, early detection, intervention, and regular follow up examinations are recommended [59, 60].

Multidisciplinary approach to management of various systemic manifestations is essential for individuals with CFC. Consultations with following specialties are recommended after diagnosis: genetics, cardiology, dermatology, ophthalmology, otolaryngology/audiology, orthopedist, and neurologist. Following testing should be performed upon diagnosis: echocardiogram, electrocardiogram, renal ultrasound, thyroid and insulin-growth-factor levels, complete blood count, and audiologic evaluation [59, 60].

Pseudoxanthoma elasticum (PXE), is a rare inherited multi-system disorder of aberrant mineralization of soft connective tissue. It is caused by mutations in the ABCC6 gene in chromosome 16, resulting in fragmentation of elastic fibers in the skin, eyes, and cardiovascular system [63–62].

PXE was originally described by the French dermatologist Rigal in 1881 although the name was coined by Darier in 1896. It is a rare disease with estimated prevalence of 1:50,000. Females are more commonly affected in 2:1 ratio [61].

Clinical features of PXE are rarely present at birth and usually manifest during the second or third decade of life [62–63]. Cutaneous findings are usually the first sign of PXE and present during childhood or adolescence . They consist of small (1–5 mm), yellowish or skin-colored papules that are initially in a reticular pattern but progressively coalesce into larger papules. Affected skin often becomes lax, wrinkled, and redundant. Initially, the lateral and posterior regions of the neck are first to be involved followed by flexural areas and periumbilical skin. Amount of skin changes often increase during pregnancy. Mucosal lesions of oral cavity, especially in the inner lower lip, and genital area can be present, resembling cutaneous changes. Cutaneous findings are not pathognomonic for PXE as similar lesions are present in other disorders including Paget’s disease, focal cutaneous elastosis, and beta-thalassemia [61]. Absence of skin findings does not exclude the diagnosis of PXE. Diagnosis can be confirmed by skin biopsy showing fragmented and clustered calcified elastic tissue in the middle and lower dermis. Although cutaneous lesions generally pose cosmetic problems, severity can predict the risk for development of ocular and cardiovascular complications with considerable morbidity and mortality.

Cardiovascular manifestations can vary and include reduced peripheral pulse (25 %), hypertension (22.5 %), angina pectoris (19 %), restrictive cardiomyopathy, mitral valve prolapse (70 %), and intermittent claudication [61]. Cardiovascular changes are caused by mineralization and fragmentation of elastic fibers of the internal elastic lamina, medial and adventitial layers of medium-sized arteries and aorta as well as myocardial tissue. Premature atherosclerosis with acute myocardial infarction and cerebrovascular accidents can also occur in PXE patients. Most patients with PXE do not experience cardiovascular problems before their third or fourth decade of life although onset as early as age 9 years have been reported. Abnormal lipoprotein composition with hypertriglyceridemia and low HDL cholesterol may occur [62–63].

Another important complication holding significant morbidity is the increased risk of gastro-intestinal (GI) hemorrhage (13–15 %). After retinal hemorrhage, GI bleeding is the second most common bleeding. The exact cause of this risk is unclear although it is postulated that spontaneous rupture of vessels may occur as in Ehlers-Danlos syndrome .

The first visible changes on fundoscopy in PXE patients are fine, yellow drusen-like appearance of the retinal pigment epithelium called peau d’orange that is most prominent temporal to the fovea. Retinal function does not appear to be affected in these areas. Peau d’orange precedes angioid streaks by 1–8 years [63].

PXE is the most common systemic disorder associated with angioid streaks. Review of large case series of angioid streaks found the association with PXE in 59–87 % of cases. Angioid streaks were first described by the English ophthalmologist Doyne in 1889 as “irregular jagged lines” that were thought to “rupture to the pigment layer of the retina” in a patient who presented after blunt trauma [62]. The term angioid streak was first coined by Knapp in 1892. In 1929, two Swedish physicians Gröenblad and Strandberg made the association between PXE and angioid streaks [63]. Angioid streaks are brownish-gray irregular lines that originate from the optic disc, may radiate outwards or be concentric around the nerve [63]. They can vary in diameter from 50 μm to several times the diameter of retinal vessels. Angioid streaks are breaks of calcified and thickened Bruch’s membrane that can progress to become full-thickness defects with atrophy of choriocapillaris, RPE , and photoreceptors. Indocyanine green angiography (ICGA) is superior to fluorescein angiography (FA) in visualizing angioid streaks. Fundus autofluorescence of angioid streaks also show areas of increased and decreased autofluorescence [62–63].

Fibrovascular tissue can grow through the defect leading to choroidal neovascularization (CNV) [63]. CNV can results in the development of subretinal fibrosis and disciform scar. Only a few cases of angioid streaks under the age of 10 have been reported, but most develop angioid streaks within 20 years after first diagnosis [63, 64]. Calcification in bruch’s membrane predisposes to breaks even with minor trauma. These breaks can lead to retinal hemorrhages independent from the presence of angioid streaks or CNV [62]. Therefore, activities with potential eye trauma should be avoided and adequate eye protection is recommended.

Other ocular features of PXE include comettial lesions, pattern-dystrophy-like changes, and optic disc drusen. Comettial lesions are halos of pigment hypertrophy with localized RPE atrophy pointing towards the posterior pole of the retina like a comet’s tail. These atrophies are small with the average diameter of 125 μm and located in the midperiphery [63]. They do not affect visual function. In contrast to angioid streaks, comettial lesions are pathognomonic for PXE [61]. Pattern dystrophy-like changes are observed in 10–70 % of PXE patients [62]. The prevalence of optic disc drusen is reported to range from 6 to 20 % compared to 0.3 % in the general population [62]. Its presence can be confirmed with ultrasound or fundus autofluorescence .

Visual prognosis of patients with PXE depends on the management of CNV. The only stage where intervention is possible is when CNV has developed. Therapeutic options include intravitreal injections of VEGF inhibitors or steroids, laser photocoagulation, and photodynamic therapy [62–63].

To date, there is no established therapy for PXE. Lifestyle factors including tobacco abstinence and healthy diet may help delay cardiovascular involvement. Anticoagulants should be prescribed with caution due to the increased risk of GI bleeding. Common sense suggests avoidance of high-risk sports such as boxing that can lead to ocular and physical trauma with devastating effects [63, 65].

Waardenburg syndrome (WS) is a heteregenous genetic syndrome cause by physical absence of melanocytes in the skin, hair, eyes and the stria vascularis of the cochlea [66]. It affects 1 in 40,000 according to population studies. There are four types. Types I, II, and III are autosomal dominant whereas Type IV is autosomal recessive. Dystopia canthorum is a feature that distinguishes Type I WS from Type II WS. Type III WS, also known as Klein-Waardenburg syndrome , is an extreme representation of Type I WS but is also characterized by musculoskeletal anomalies. Type IV WS (Shah-Waardenburg) is associated with congenital aganglionic megacolon (Hirschsprung disease) . Fulfillment of two major criteria or one major and two minor criteria is required for diagnosis. Major criteria include characteristic white forelock (hair depigmentation), pigmentary anomalies of iris, congenital sensorineural deafness, dystopia canthorum, or an affected first degree relative. Minor criteria are depigmented maculars or patches, synophrys, broad nasal root, nose hypoplasia, and early graying of hair by age 35. Genes involved include PAX3, MITF, SOX10, EDN3, and EDNRB genes [66–68].

White forelock, which is usually midline, is found in 30–40 % of patients. It can be present at birth or may develop or fade with age and also be variable in severity ranging from few strands to clump of hair being affected. Premature graying can occur in approximately 10 % of individuals. Pigmentation defects can affect eyebrows and eyelashes as well [66].

Hypopigmentation of skin is congenital and can be found on the face, trunk, or extremities. It may be associated with adjacent white forelock. Hyperpigmentation can develop in previously hypopigmented area, especially along the borders. If depigmented patches are extensive, piebaldism due to KIT gene mutation should be suspected, especially in a patient with normal hearing [66].

Sensorineural hearing loss, which is dues to malformations of organ of Corti, is most commonly seen in type II WS . It is congenital and usually nonprogressive. It can be unilateral or bilateral and vary in severity from mild to profound loss.

Musculoskeletal abnormalities seen in Type III WS are usually abnormalities of upper extremities, flexion contractures, and syndactyly. Hirschsprung disease seen in Type IV WS and is due to mutations in EDN3 and EDNRB genes [66].

Dystopia canthorum is the most distinguishing feature of Type I WS, being present in 99 % of affected individuals. There is appearance of blepharophimosis with fusion of inner eyelids medially, resulting in reduced medial scleral show. The inferior lacrimal puncta are laterally displaced. Inner canthal, interpupillary and outer canthal distances are greater than normal, indicative of hypertelorism in addition to telecanthus. The W index is a formula based on measurements of these distances. W index value of greater 2.07 is indicative of dystopia canthorum [66].

Iris heterochromia can be partial or complete, which the hypochromic iris being the affected eye due to absence of melanocytes and deficient iris stroma. If partially affected, differently colored areas are sharply demarcated and usually in radial segments (Fig. 8.6). Anterior segment optical coherence tomography revealed that hypopigmented iris were thinner and had shallower crypts compared to normal iris [66, 69].

Hypopigmentation of the choroid can also be seen in a sectoral or diffuse pattern. Posterior segment optical coherence tomography showed the retina to be normal in structure although the subfoveal choroid in hypopigmented region was slightly thinner compared with the opposite normal choroid. Fundus autofluorescence demonstrated mild hyperautofluorescence (scleral unmasking) in hypopigmented choroid with no lipofuscin abnormality. Visual acuity is known to be preserved unless with presence of foveal hypoplasia or amblyopia. Strabismus is more common in WS1 compared to the general population [66, 69].

Xeroderma pigmentosa (XP) is a heterogeneous group of autosomal recessive disorders caused by defective UV-radiation induced damage repair. When DNA is exposed to UV radiation, multiple nucleic acid based photobyproducts form and serve as substrates for DNA repair in the nucleotide excision repair (NER) process. Damaged DNA is recognized via the transcription-coupled repair (TCR) pathway and the global genome repair (GGR) pathway. Mutations in any of the proteins involved in the NER, TCR, and GGR pathways lead to abnormalities in DNA repair and manifest as clinical syndromes with overlapping features including XP, Cockayne syndrome (CS), and trichothidystrophy (TTD) [70].

Different complementation groups (A–G) have been described for XP, each with distinct DNA excision repair defects. XP variant (XPV) is clinically similar to other subtypes but does not involve a mutation of the NER system. XPV patients may have increased long-term survival compared to the other subtypes of XP . Prevalence varies depending on geography with XPC being the most common complement type in the United States, Europe and North Africa whereas XPA is the most common type in Japan [70].

Classic phenotype of XP presents in the early childhood as freckling by the age of two, severe burning with minimal sun exposure, and skin cancer manifesting at an early age [70]. Skin often undergoes premature aging with progressive atrophy, telangiectasias, and abnormal lentiginous pigmentation with intermixed hypopigmented and hyperpigmented areas. All complement types of XP have photosensitivity and increased cancer risk although some types are less severe than others. Individuals with XPC, XPE, and XPV subtypes may tan and acquire abnormal pigmentation but experience less severe sun burning after minimal sun exposure [70].

XP patients have a >10,000 fold risk over their lifetime of developing nonmelanocytic skin cancer and >2000 fold risk for melanoma compared to the general population. The median age for the first diagnosis of skin cancer is 9 years (age range 1–32 years) for non-melanocytic skin cancer and 22 years for melanoma (age range 2–47 years) [70]. Skin cancer accounts for the highest number of disease-related deaths in XP patients. XP patients also have a 50-fold increased risk of developing brain tumors such as medulloblastoma, glioblastoma, spinal cord astrocytoma, and schwannoma. XP patients who smoke have a higher risk of lung cancer compared to the general population [70].

The nervous system is affected in a significant subset of XP patients. Although the nervous system does not receive direct UV radiation exposure, unrepaired oxidative damage may be a possible cause of the neurodegeneration that is seen in 24 % of XP patients. The most commonly affected subtypes are XPD and XPA. It is rarely seen in subtypes XPC and XPE [70]. Signs include loss of intellectual functioning, impaired hearing, abnormal speech, areflexia, ataxia, and peripheral neuropathy. Neuroimaging may reveal neuronal loss, cortical atrophy and ventricular dilatation without inflammation.

Ocular involvement in XP is common, ranging from 40 % to 91 % in literature review [71]. Ocular tissues that are exposed to ultraviolet radiation are involved in XP, and symptoms appears early in childhood. By the age of 10 or less, most patients have some degree of ocular morbidity. The earliest report of ocular symptoms was described by Hebra and Kaposi in the late nineteenth century when they noted xerosis, ectropion, corneal ulcers and opacities in two patients with XP [72]. Ocular manifestations can be divided into the following categories: structural eyelid abnormalities, neoplasms of ocular surface and eyelids, ocular surface inflammation, and corneal abnormalities [71].

Eyelid involvement, with both benign and malignant lesions, is seen in approximately 80 % of patients [73]. In one the largest report of 87 XP patients, 11 % had a history of ocular surface and skin cancer with the median age of onset at 16 years [71]. Atrophic skin changes can lead to lagophthalmos, ectropion and less commonly, entropion [71]. Tear film and tear production is often abnormal due to keratinization of lid margins and structural lid abnormalities. Twenty percent of patients had conjunctival melanosis, but these lesions rarely developed into malignant melanoma [71]. Ocular surface problems include conjunctivitis, pterygium, band-like keratopathy, conjunctival neoplasms and xerosis [51]. Exposure keratopathy can lead to corneal opacification, pannus formation, and neovascularization. Ocular surface malignancy can be present in 10 % of patients.

There is currently no cure for XP. Consistent UV radiation protection is imperative and can substantially reduce the number of skin cancers. Protection consists of layered clothing, ample sunscreen and eye protection, including fully shielded eyewear and adequate lubrication. Decreasing UV radiation exposure may not decrease neurodegenerative effects. Vitamin D supplementation should be initiated to offset sun avoidance. Systemic treatment with retinoids has been reported with some benefit. Regular examination of skin and eyes are required with early excision of suspicious lesions The most commonly affected subtypes are XPD and XPA. It is rarely seen in subtypes XPC and XPE [70].

Similar to XP, Cockayne syndrome (CS) is an autosomal recessive disorder of severe photosensitivity and premature aging caused by mutations in CSA (25 %) or CSB (75 %), which are involved in the NER pathway. Individuals with CS have photosensitivity but do not develop abnormal pigmentation and also do not have increased risk of cutaneous malignancy [74].

The phenotypic spectrum of CS can be described into four types: CS type I (classic), CS type II (severe form), CS type III (mild), and Xeroderma pigmentosum-Cockayne syndrome (XP-CS) .

CS type I has moderate phenotype with normal development until age two after which there is neurodegeneration leading to death in the first or second decade of life. By the time the disease has become manifest, height, weight, and head circumference are below the fifth percentile. There is progressive impairment of vision, hearing, and decline in central and peripheral nervous system function leading to severe disability. Severe dental caries occur in up to 86 % of patients. Neurologic symptoms and signs include spasticity, abnormal gait or inability to walk, incontinence, tremor, abnormal speech, seizures, poor feeding, and muscle atrophy. Many CS patients exhibit sociable and outgoing behavior. Neurodegeneration seen in CS is due to demyelination, and patients often have increased deep tendon reflexes unlike patients with XP. Neuroimaging shows cerebral atrophy, ventricular dilation, calcification of the basal ganglia and cerebral cortex. Neuropathology shows characteristic “tigroid” pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition with relative preservation of neurons. Skin manifestations consist of anhidrosis and butterfly malar rash after sun exposure. Facial dysmorphism with “bird-like” appearances have been described. Abnormal renal function and elevated liver function tests can be present in 10 % of patients. Undescended testes and absent sexual maturation. No individuals with CS type I or type II have been known to reproduce [74]. Diagnosis of CS I is made clinically [Table 8.2] [74]. In an older child, CS I is suggested when both major criteria are present and three minor criteria are present. In an infant, it can be diagnosed when both major criteria are present, especially with increased cutaneous photosensitivity .

Type II is more severe and manifests with growth failure at birth with little to no postnatal neurologic development. Arthrogryposis or early postnatal contractures of the spine and joints are commonly seen. Congenital cataracts and other structural anomalies of the eye may be present in 30 %. Death occurs in the first decade of life. CS type II overlaps clinically with cerebrooculofacioskeletal syndrome (COFS) [74].

Type III has milder symptoms and later onset of disease. A difficult but successful pregnancy has been reported in a young woman with CS type III.

XP-CS has features of XP including facial freckling and early skin cancers in addition to features of CS with intellectual disability, spasticity, short stature, and hypogonadism .

The classic ocular finding in Cockayne syndrome is pigmentary retinopathy, which was initially described by Cockayne in 1936 [73]. It is reported in 60–100 % of patients in the literature and is most commonly seen as a “salt and pepper” fundus [73]. Bony spicules and optic atrophy have been reported as well. Electroretinograms may show diminished scotopic and photopic responses, depending on the severity of fundus changes and the age of patients [73]. Cataracts of various types, including nuclear, cortical, and posterior subcapsular, are seen in 15 % to 36 % of patient, often with CS type II [73, 74]. Pupils can be miotic and do not respond well to mydriatics, which can complicate intraocular surgery. Enophthalmos is common and is due to the lack of subcutaneous orbital fat [73, 74]. Other ocular findings include dryness, strabismus, nystagmus, and refractive error [74]. Predictors of poor prognosis include cataracts noted at birth or within the first 3 years of life, microphthalmia or iris hypoplasia [73].

Treatment of manifestations is the mainstay of management for patients with CS and includes individualized educational programs for developmental delay, physical therapy to maintain ambulation, medications for spasticity and tremor, gastrotomy tube placement as needed, treatment of hearing loss, and use of sunscreens and sunglasses for photosensitivity. Surgery for cataracts and ophthalmologic complications are performed as in the general population. Annual surveillance for complications such as hyptenstion, renal and hepatic dysfunction, vision and hearing is recommended [74].

Trichothiodystrophy (TTD) is a rare autosomal recessive disease of defective transcription in DNA repair, in which patients have brittle sulphur deficient hair [75]. Patients with TTD typically display a wide variety of clinical features, including abnormal hair, intellectual impairment, decreased fertility, short stature, and ichthyosis. Several acronyms have been created to describe the cutaneous findings of trichothiodystrophy. PIBIDS stands for photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature [21]. Other acronyms include IBIDS and BIDs. To date, four genes have been identified as causing TTD: XPD, XPB, TTDA, and TTDN1 [75].

Patients commonly have sparse, brittle, and friable sulfur-deficient hair (96 %). The hair shows tiger tail banding (striped light and dark pattern) under a polarizing microscope [75]. The majoritiy of patients with TTD have skin findings, most commonly being ichthyosis (65 %). Second most frequently seen skin manifestation is photosensitivity (42 %), but similar to Cockayne syndrome, TTD is not associated with increased risk for malignancy or abnormal pigmentation. Premature aging can frequently be seen. Nail abnormalities including onychodystrophy, brittle nails, and kolionychia are commonly present [75].

Developmental delay and intellectual impairment has been reported in 86 % of patients [75]. Other neurologic findings described include microcephaly, abnormal gait, and spasticity. Neurodegeneration is thought to be due to abnormal myelin development. Neuroimaging shows demyelination and may also show cortical heterotopias, partial agenesis of the corpus callosum, perimedullary fibrosis of the spinal cord, and intracranial calcifications.

Facial dysmorphism was reported in two-third of patients with TTD . Microcephaly, large or protruding ears, and micrognathia can be seen. Growth abnormalities leading to short stature and poor weight gain can be seen in up to 80 % of patients with TTD. Reproductive abnormalities include hypogonadism, cryptorchidism, delayed pubertal development and partial panhypopituitaris [75].

Eye findings are found in approximately 51–94 % in studies of TTD patients [75, 76]. Ocular manifestations include refractive error (12–66 %), nystagmus (14–38 %), cataracts (29–62 %), strabismus (10–19 %), dry eyes (31 %), ectropion, and pigmentary retinopathy [75, 76]. Microcornea and microphthalmias can be seen as well. Cataracts are usually bilateral and can vary in severity and may not necessarily require removal [76]. Brittle eyelashes can lead to keratitis due to their abnormal orientation [73]. Retinal degeneration, although not commonly seen, may be a late-occurring phenotype and should be monitored [76].

Effective management of multisystem abnormalities of TTD requires a multidisciplinary approach [75].

Rothmund-Thomson syndrome (RTS), also known as poikiloderma congenitale , is a rare autosomal recessive disorder of abnormal skin, hair, bone and increased risk for cancer.

The initial description of RTS was in 1868 by the German ophthalmologist Rothmund who reported ten children with poikiloderma, growth retardation, and rapidly progressive bilateral cataracts [77]. Subsequently, the English dermatologist Thomson described three children with similar symptoms of poikiloderma and skeletal abnormalities [78]. The name Rothmund-Thomson syndrome was first coined by Taylor in 1957 who also reported a group of patients with similar symptoms [79].

Two forms of RTS have been described: type I RTS, characterized by poikiloderma, ectodermal dysplasia, juvenile cataracts, and negative for the RECQL4-mutation (DNA helicase gene); and type II RTS, characterized by poikiloderma, skeletal abnormalities and increased risk of osteosarcoma due to RECQL4 mutations [77].

Skin is typically normal at birth. Rash of RTS develops between age 3 and 6 months as erythema and blistering of cheeks and face that spreads to the extensor surfaces of extremities and buttocks. Rash typically spare the trunk and abdomen. This evolves over months to years into a chronic pattern of poikiloderma which consist of reticulated hypo- and hyperpigmentation, telangiectasias, and areas of punctate atrophy [80]. This chronic phase usually persists throughout life If the rash is atypical in appearance or distribution, a diagnosis of probably RTS can be made with presence of two other following features: sparse scalp hair, eyelashes or brows, short stature, gastrointestinal disturbances (chronic vomiting or diarrhea), skeletal abnormalities, dental abnormalities, nail abnormalities, hyperkeratosis , juvenile bilateral cataracts, and skin (basal cell or squamous cell carcinoma) or bone cancers (osteosarcoma). Benign and malignant hematologic abnormalities have been reported and includes: isolated anemia, neutropenia, myelodysplasia, aplastic anemia, and leukemia. Prevalence of osteosarcoma is as high as 30 % in patients with RTS with median age at diagnosis of 11 years [80].

The most common ocular sign of RTS is bilateral juvenile cataracts that are present in up to 70 % of cases [81]. Cataracts are usually subcapsular and may present between ages 3 and 7 years although cases as early as few months of life to early adulthood have been reported [77]. Most reports of bilateral cataracts are from Europe. A more recent international cohort of 41 patients had only two patients with cataracts [82]. Madarosis or sparseness of eyelashes and eyebrows are frequently seen . Other less common ocular features include exophthalmos, corneal scleralization, blue sclera, and bilateral congenital glaucoma [73, 81].

Surveillance for complications and cancer screening is key to management of patients with RTS. Avoidance of excessive sun exposure and liberal use of sunscreen are recommended to prevent skin cancer. Calcium and vitamin D supplements are warranted in patients with osteopenia or history of fractures [80].

Classic cutaneous findings of IP occur in four stages within the first 2 years of life: vesicular, verrucous, hyperpigmented, and atrophic [84] (Fig. 8.7). The first vesicular stage is characterized by small, scattered blisters on an erythematous base that develop along the lines of Blashko. This stage is most prominent in the first 6 months of life. The verrucous phase is characterized by verrucous, hyperkeratotic, linear lesions, mainly on the limbs. The hyperpigmented stage usually occurs after resolution of the verrucous phase. Hyperpigmented streaks and whorls that respect Blaschko’s lines occur mainly on the trunk and fades in adolescence. Finally, the hypopigmented/atrophic phase occurs last where patches and streaks of pale, hairless, and atrophic skin are present. IP is also commonly associated with alopecia, nail dystrophy, and loss of sweat glands. Hypodontia or anodontia (partial or complete absence of teeth), microdontia and abnormally shaped teeth may be seen [84].

Central nervous system (CNS) abnormalities can also be present in patients with IP as CNS is also of ectodermal origin. In an analyzed literature data of 1393 IP patients from the period of 1993 to 2012, CNS anomalies were diagnosed in 30 % of patients [85]. Most common CNS manifestations were seizures, motor impairment, microcephaly, and developmental delay [85]. The most frequently seen CNS lesions on brain imaging were brain infarcts, atrophy, and corpus callosum lesions [85].

Ocular involvement occurs in 35–77 % of studied populations [86]. In contrast to cutaneous findings that usually attenuate with time, ocular involvement persists throughout the lifetime of patients with the prevalence of blindness reported to be between 7 and 23 % [83]. The most problematic ocular manifestation is in the retina, affecting the peripheral vascularization of the retina and retinal pigment epithelium [83]. Vaso-occlusions that predominantly affect the arteries lead to peripheral nonperfusion and irreversible ischemia, which results in a cascade of events: proliferation of new blood vessels, exudation, hemorrhage, tractional retinal detachment, and even to a retrolental mass at its late stage if left untreated [83, 87]. Vasculopathies may also occur in the macula where fundus appearance may be normal but fluorescein angiography shows nonperfusion and capillary remodeling [88]. Other ophthalmologic findings in IP are secondary and include cataract, strabismus, nystagmus, and anterior segment abnormalities [89]. Strabismus is most often due to retinal pathology or poor vision [90].

Patients with IP are recommended to undergo examination by a pediatric ophthalmologist or retinal specialist at birth, at least monthly for the first 3–4 months, at 3-month intervals for 1 year, and twice yearly up to 3 years [84, 90]. Fluorescein angiography is crucial in evaluating for areas of nonperfusion and vascular abnormalities.

Laser photocoagulation when performed in the early stages before neovascularization ensues can arrest the development of proliferative vitreoretinopathy and retinal detachment [91].

Treatment depends on the manifestations of disease. Patients may need treatment of blisters and skin infections, neurologic assessment and management of seizures, dental care which may include implants at an early age, and developmental programs and special education as needed for developmental delay.

Linear nevus sebaceous lesions were initially described by Jadassohn in 1895 as congenital cutaneous lesions in linear distribution. He described the lesions as organoid nevus because they may contain any or all components of the skin. Subsequently Robinson introduced the term nevus sebaceous of Jadassohn and suggested that malignant tumors, particularly basal cell carcinoma, can arise in the area of sebaceous nevus. In 1957, Schimmelpenning noted the association of these skin lesions with abnormalities of the CNS , skeletal system and eyes. In 1962, Feuerstein and Mims reported cutaneous lesions and seizures suggesting that the condition is a neurocutaneous syndrome [92, 93].