Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this entry) is characterized by partial or total alopecia, dystrophy of the nails, hyperpigmentation of the skin (especially over the joints), and clubbing of the fingers. Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is wiry, brittle, patchy, and pale; progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. The clinical manifestations are highly variable even within the same family.

Age: The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.

Sex: The male-to-female ratio is approximately 3:1.

Physical: The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.

Cutaneous findings:

The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common.

The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face. Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).

Nail findings:

Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.

Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.

Mucosal findings:

Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.

Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.

Bone marrow failure:

Approximately 90% have peripheral cytopenia of one or more lineages. In some cases, this is the initial presentation, with a median age of onset of 10 years.

Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.

Pulmonary complications:

Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.

The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (e.g., busulfan) and that they have their lungs shielded from radiation during BMT.

Increased risk of malignancy:

Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia.

The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma.

Malignancy tends to develop in the third decade of life.

Neurologic system findings: Patients may have learning difficulties and mental retardation.

Ophthalmic system findings: DKC reportedly is associated with conjunctivitis, blepharitides, and pterygium. Lacrimal duct stenosis resulting in epiphora (i.e., excessive tearing) occurs in approximately 80% of patients.

Skeletal system findings: Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.

Gastrointestinal system findings: These may include esophageal webs, hepatosplenomegaly, enteropathy, and cirrhosis.

Genitourinary system findings:: Hypospastic testes, hypospadias, and ureteral stenosis are reported.

Female carriers: Female carriers of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

DKC can be characterized by cutaneous pigmentation, premature graying, of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans.

This condition is characterised by symmetrical lesions on the temples resembling forceps marks. It is characterized a puckered skin due to a virtual absence of subcutaneous fat. It is apparent at birth. Other lesions that may be present include puffy, wrinkled skin around the eyes and/or abnormalities of the eyelashes, eyebrows, and eyelids. The eyebrows may be up slanting or outward slanting. Occasionally the bridge of the nose may appear flat, while the tip may appear unusually rounded. The chin may be furrowed. The upper lip may be prominent with a down turned mouth. Other features that have been reported include dysplastic and low set ears, linear radiatory impressions on the forehead and congenital horizontal nystagmus.

Those with the Setleis syndrome may be missing eyelashes on both the upper and lower lids or may have multiple rows of lashes on the upper lids but none on the lower lids.A possible association with intra abdominal cancer has been reported but to date this has not been confirmed in other studies.

The skin lesions evolve through characteristic stages:

1. blistering (from birth to about four months of age),

2. a wart-like rash (for several months),

3. swirling macular hyperpigmentation (from about six months of age into adulthood), followed by

4. linear hypopigmentation.

Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays/mental retardation are occasionally seen.

Discolored skin is caused by excessive deposits of melanin (normal skin pigment).

Most newborns with IP will develop discolored skin within the first two weeks.

The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines.

The discoloration sometimes fades with age.

Neurological problems can include: cerebral atrophy, the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex.

About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, mental retardation, and seizures.

They are also likely to have visual problems, which can include: crossed eyes, cataracts, and severe visual loss.

Dental problems are common, and include missing or peg-shaped teeth - patients with IP often keep milk teeth into adult life.

Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary nipples.

Skeletal and structural anomalies can occur in approximately 14% of patients, including:

- Somatic asymmetry,

- Hemivertebrae,

- Scoliosis,

- Spina bifida,

- Syndactyly,

- Acheiria (congenital absence of the hands - note: other limbs may be affected),

- Ear anomalies,

- Extra ribs,

- Skull deformities,

- Primary pulmonary hypertension,

- Cardiopulmonary failure

Individuals affected by an ED syndrome frequently have abnormalities of the hair follicles. Scalp and body hair may be thin, sparse, and very light in color, even though beard growth in affected males may be normal. The hair may grow very slowly or sporadically and it may be excessively fragile, curly, or even twisted.

Membranous aplasia cutis is a cutaneous condition, a type of aplasia cutis congenita, which can be seen along the embryonic fusion lines of the face.

Fingernails and toenails may be thick, abnormally shaped, discolored, ridged, slow-growing, or brittle. The cuticles may be prone to infections.

Aplasia cutis congenita (ACC) is a rare disorder characterized by congenital absence of skin. Frieden classified ACC in 1986 into 9 groups on the basis of location of the lesions and associated congenital anomalies. The scalp is the most commonly involved area with lesser involvement of trunk and extremities. Frieden classified ACC with fetus papyraceus as type 5. This type presents as truncal ACC with symmetrical absence of skin in stellate or butterfly pattern with or without involvement of proximal limbs.]It is the most common congenital cicatricial alopecia, and is a congenital focal absence of epidermis with or without evidence of other layers of the skin.

The exact etiology of ACC is still unclear but intrauterine infection by varicella or herpes virus, drugs such as methimazole, misoprostol, valproate, cocaine, marijuana etc., fetus papyraceus, feto-fetal transfusion, vascular coagulation defects, amniotic membrane adherence, abnormal elastic fiber biomechanical forces and trauma are implicated. It can be associated with Johanson-Blizzard syndrome, Adams-Oliver syndrome, trisomy 13, and Wolf-Hirschhorn syndrome.

It can also seen with exposure to methimazole and carbimazole in utero. This dermatological manifestation has been linked to Peptidase D haploinsufficiency and a deletion in Chromosome 19.

Two key features of AOS are aplasia cutis congenita with or without underlying bony defects and terminal transverse limb defects. Cutis aplasia congenita is defined as missing skin over any area of the body at birth; in AOS skin aplasia occurs at the vertex of the skull. The size of the lesion is variable and may range from solitary round hairless patches to complete exposure of the cranial contents. There are also varying degrees of terminal limb defects (for example, shortened digits) of the upper extremities, lower extremities, or both. Individuals with AOS may have mild growth deficiency, with height in the low-normal percentiles. The skin is frequently observed to have a mottled appearance (cutis marmorata telangiectatica congenita). Other congenital anomalies, including cardiovascular malformations, cleft lip and/or palate, abnormal renal system, and neurologic disorders manifesting as seizure disorders and developmental delay are sometimes observed. Variable defects in blood vessels have been described, including hypoplastic aortic arch, middle cerebral artery, pulmonary arteries. Other vascular abnormalities described in AOS include absent portal vein, portal sclerosis, arteriovenous malformations, abnormal umbilical veins, and dilated renal veins.

Gerodermia osteodysplastica is characterized by symptoms and features which affect the connective tissues, skin and skeletal system.

These are: wrinkly, loose skin over the face, abdomen, and extremites (hands, feet) on the dorsal sides usually worsened by chronic joint laxity and hyperextensibility; fragmented elastic fibers of the skin that are reduced in number, with disorientation of collagen fibers; osteopenia and osteoporosis, with associated fractures; malar hypoplasia (underdeveloped cheek bone), maxillary hypoplasia (underdeveloped upper jaw), mandibular prognathism (protrusion of the lower jaw and chin), bowed long bones, platyspondyly (flattened spine) related to vertebral collapse; kyphoscoliosis (scoliosis with kyphosis, or "hunch back"), metaphyseal peg (an unusual outgrowth of metaphyseal tissue which protrudes into the epiphyseal region of the bone, near the knee); and the overall physical effects and facial appearance of dwarfism with premature aging.

Other features and findings include: intrauterine growth retardation, congenital hip dislocations, winged scapulae (shoulder blades), pes planus (fallen arches), pseudoepiphyses of the second metacarpals (upper bone of the fingers), hypotelorism (close-set eyes), malformed ears,

developmental delay,

failure to thrive and abnormal electroencephalograph (EEG) readings.

Dental and orthodontal abnormalities in addition to maxillary hypoplasia and mandibular prognathism have also been observed in gerodermia osteodysplastica. Including malocclusion of the dental arches (the maxilla and mandible), radiological findings in some cases have indicated significant overgrowth of the mandibular premolar and molar roots;

hypercementosis (overproduction of cementum) of the molars and maxillary incisors; enlarged, funnel-shaped mandibular lingula (spiny structures on the ramus of the mandible); and a radiolucent effect on portions of many teeth, increasing their transparency to x-rays.

The key affected features of this condition are described in its name.

Scalp: There are raised nodules over the posterior aspect of the scalp, covered by scarred non-hair bearing skin.

Ears: The shape of the pinnae is abnormal, with the superior edge of the pinna being turned over more than usual. The size of the tragus, antitragus and lobule may be small.

Nipples: The nipples are absent or rudimentary. The breasts may be small or virtually absent.

Other features of the condition include:

Dental abnormalities: missing or widely spaced teeth

Syndactyly: toes or fingers may be partially joined proximally

Renal abnormalities: renal hypoplasia, pyeloureteral duplication

Eye abnormalities: Cataract, coloboma of the iris and asymmetric pupils.

HED2 is suspected after infancy on the basis of physical features in most affected individuals. GJB6 is the only gene known to be associated with HED2. Targeted mutation analysis for the four most common GJB6 mutations is available on a clinical basis and detects mutations in approximately 100% of affected individuals. Sequence analysis is also available on a clinical basis for those in whom none of the four known mutations is identified.

Clinically, three distinct patterns of palmoplantar keratoderma may be identified: diffuse, focal, and punctate.

Focal facial dermal dysplasia (FFDD) is a rare genetically heterogeneous group of disorders that are characterized by congenital bilateral scar like facial lesions, with or without associated facial anomalies. It is characterized by hairless lesions with fingerprint like puckering of the skin, especially at the temples, due to alternating bands of dermal and epidermal atrophy.

This condition is also known as Brauer syndrome (hereditary symmetrical aplastic nevi of temples, bitemporal aplasia cutis congenita, bitemporal aplasia cutis congenita: OMIM ) and Setleis syndrome (facial ectodermal dysplasia: OMIM ).

Diffuse palmoplantar keratoderma is a type of palmoplantar keratoderma that is characterized by an even, thick, symmetric hyperkeratosis over the whole of the palm and sole, usually evident at birth or in the first few months of life. Restated, diffuse palmoplantar keratoderma is an autosomal dominant disorder in which hyperkeratosis is confined to the palms and soles. The two major types can have a similar clinical appearance:

- "Diffuse epidermolytic palmoplantar keratoderma" (also known as "Palmoplantar keratoderma cum degeneratione granulosa Vörner," "Vörner's epidermolytic palmoplantar keratoderma", and "Vörner keratoderma") is one of the most common patterns of palmoplantar keratoderma, an autosomal dominant condition that presents within the first few months of life, characterized by a well-demarcated, symmetric thickening of palms and soles, often with a "dirty" snakeskin appearance due to underlying epidermolysis.

- "Diffuse nonepidermolytic palmoplantar keratoderma" (also known as "Diffuse orthohyperkeratotic keratoderma," "Hereditary palmoplantar keratoderma," "Keratosis extremitatum progrediens," "Keratosis palmoplantaris diffusa circumscripta," "Tylosis," "Unna–Thost disease", and "Unna–Thost keratoderma") is inherited as an autosomal dominant condition and is present from infancy, characterized by a well-demarcated, symmetric, often "waxy" keratoderma involving the whole of the palms and soles.

Beare–Stevenson cutis gyrata syndrome is a rare genetic disorder characterized by craniosynostosis (premature fusion of certain bones of the skull, sometimes resulting in a characteristic 'cloverleaf skull'; further growth of the skull is prevented, and therefore the shape of the head and face is abnormal) and a specific skin abnormality, called cutis gyrata, characterized by a furrowed and wrinkled appearance (particularly in the face and on the palms and soles of the feet); thick, dark, velvety areas of skin (acanthosis nigricans) are sometimes found on the hands and feet and in the groin.

Additional signs and symptoms of Beare–Stevenson cutis gyrata syndrome can include a blockage of the nasal passages (choanal atresia), overgrowth of the umbilical stump, and abnormalities of the genitalia and anus. The medical complications associated with this condition are often severe and may well be life-threatening in infancy or early childhood.

Microphthalmia–dermal aplasia–sclerocornea syndrome (also known as "MIDAS syndrome") is a condition characterized by linear skin lesions.

MLS is a rare X-linked dominant male-lethal disease characterized by unilateral or bilateral microphthalmia and linear skin defects in affected females, and in utero lethality for affected males. It can be associated with "HCCS", but mutations in the MCCS gene cause Microphthalmia with Linear Skin Defects Syndrome.

Incontinentia pigmenti (IP) is a rare genetic disorder that affects the skin, hair, teeth, nails, and central nervous system. It is named from its appearance under a microscope. It is also known as Bloch–Siemens syndrome, Bloch–Sulzberger disease, Bloch–Sulzberger syndrome, melanoblastosis cutis, and nevus pigmentosus systematicus.

It is characterized by skin abnormalities that begin in childhood, usually a blistering rash which heals, followed by the development of harder skin growths. The skin may develop grey or brown patches which fade with time. Other symptoms can include hair loss, dental abnormalities, eye abnormalities that can lead to vision loss, and lined or pitted fingernails and toenails. Associated problems can include delayed development, intellectual disability, seizures, and other neurological problems. There is no specific treatment, individual conditions must be managed by specialists.

It is characterized by skin that is loose, hanging, wrinkled, and lacking in elasticity. The loose skin is often most noticeable on the face, resulting in a prematurely aged appearance. The affected areas of skin may be thickened and dark. In addition, the joints are loose (hypermobile) because of lax ligaments and tendons. When cutis laxa is severe, it can also affect the internal organs. The lungs, heart (supravalvular pulmonary stenosis), intestines, or arteries may be affected with a variety of severe impairments. In some cases, hernias and outpouching of the bladder can be observed. Patients also present with whites of the eyes that are blue.

Gerodermia osteodysplastica (GO), also called geroderma osteodysplasticum and Walt Disney dwarfism, is a rare autosomal recessive connective tissue disorder included in the spectrum of cutis laxa syndromes.

Usage of the name "Walt Disney dwarfism" is attributed to the first known case of the disorder, documented in a 1950 journal report, in which the authors described five affected members from a Swiss family as having the physical appearance of dwarves from a Walt Disney film.

The terms "geroderma" or "gerodermia" can be used interchangeably with "osteodysplastica" or "osteodysplasticum", with the term "hereditaria" sometimes appearing at the end.

Common symptoms include:

- Excess keratin in nail beds and thickening of the nails

- Hyperkeratosis on hands and feet

- Oral lesions that look like thick white plaques

- Steatocystoma multiplex

- Pain

- Blisters

Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium (cutis aplasia congenita), transverse defects of the limbs, and mottling of the skin.

Phakomatosis pigmentovascularis is subdivided into five types:

- Type 1 PWS + epidermal nevus

- Type 2 (most common): PWS + dermal melanocytosis +/- nevus anemicus

- Type 3: PWS + nevus spilus +/- nevus anemicus

- Type 4: PWS + nevus spilus + dermal melanocytosis +/- nevus anemicus

- Type 5: CMTC (Cutis marmorata telangiectatica congenita) + dermal melanocytosis

They all can contain capillary malformation. Type 2 is the most common and can be associated with granular cell tumor. Some further subdivide each type into categories A & B; with A representing oculocutaneous involvement and subtype B representing extra oculocutaneous involvement. Others have proposed fewer subtypes but currently this rare entity is mostly taught as having five subtypes currently.

Phakomatosis pigmentovascularis is a rare neurocutanous condition where there is coexistence of a capillary malformation (port-wine stain) with various melanocytic lesions, including dermal melanocytosis (Mongolian spots), nevus spilus, and nevus of Ota.