Other Genodermatoses (Chapter 63)

MEN Syndromes
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Terms in this set (39)
Multiple endocrine neoplasia (MEN) refers to a group of disorders marked by the presence of neoplasia or hyperplasia in two or more endocrine organs, often in association with mucocutaneous findings. Three major MEN syndromes - termed types 1, 2A, and 2B - have been clinically and genetically defined and are described in Table 63.21.
Mucocutaneous features are most prominent in MEN types 1 and 2B. In type 1, multiple facial angiofibromas and collagenomas are present in the majority of affected individuals (Fig. 63.1), and lipomas are another common finding2,3. Compared to those in tuberous sclerosis, facial angiofibromas in MEN 1 tend to be smaller and fewer in number, and they are more likely to arise on the upper lip and its vermilion border in addition to the nose and medial cheeks. Although melanoma has been reported in patients with MEN 1 and there is evidence that MEN1 expression is frequently lost in sporadic melanomas4,5, it remains unclear whether individuals with this syndrome have an increased risk of melanoma.
MEN 2B is notable for multiple mucosal neuromas, especially of the conjunctivae, lips, and anterior tongue (Fig. 63.2). These lesions, which may be present at birth or develop during early childhood, are considered relatively specific for this diagnosis. However, mucosal neuromas are also occasionally observed in patients with the PTEN hamartoma tumor syndrome (see below). Cutaneous neuromas are rare in MEN 2B and when present are usually in a perinasal location.
PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders with overlapping clinical features caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Cowden syndrome (CS) represents the most common phenotype of PHTS and is characterized by multiple hamartomas of ectodermal, mesodermal, and endodermal origin. Macrocephaly and mucocutaneous lesions (e.g. tricholemmomas, acral keratoses, oral papillomas) are the most constant and characteristic features6. Up to 85% of CS patients develop at least one malignant neoplasm, most often of the breast, thyroid, or endometrium7.

In 1963, Lloyd and Dennis reported a multisystem disorder with characteristic mucocutaneous lesions and tumors of the breast, thyroid, and gastrointestinal tract6. They named the disorder "Cowden disease" after their first patient.

CS is probably more common than is reflected by the number of cases reported, because the clinical findings can be subtle. It is inherited as an autosomal dominant trait with variable expressivity; a female predominance has been noted in some series8. Most of the reported patients have been Caucasian, and it is estimated to affect 1 in 200 000 individuals
Heterozygous germline mutations in the tumor suppressor gene PTEN are found in most patients with CS as well as other conditions within the PHTS spectrum10, which includes Bannayan-Riley-Ruvalcaba syndrome (BRRS), SOLAMEN syndrome (segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus; see Ch. 62), and an autism/macrocephaly syndrome. Of note, there is significant overlap in the clinical findings of CS and BRRS (Table 63.3). Identical mutations have been found in patients with CS and BRRS, and in some families both CS and BRRS phenotypes are observed.
The PTEN protein is a lipid and protein phosphatase that plays a role in cell-cycle regulation and apoptosis11. In particular, PTEN downregulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that promotes cellular proliferation and survival (see Fig. 55.3). As in other autosomal dominant disorders caused by a defective tumor suppressor gene, hamartomas and neoplasms typically result from a "second hit" somatic mutation that inactivates the remaining allele of the gene (loss of heterozygosity). In PHTS, this leads to excessive mTOR signaling in affected tissues, in particular those with physiologic proliferation, such as the epidermis, oral and gastrointestinal mucosa, and thyroid and breast epithelium. PTEN also has phosphatase-independent activities and nuclear functions independent of the PI3K/AKT/mTOR pathway11
Cutaneous involvement occurs in >80% of patients with CS and often serves as an early sign of the disorder. Characteristic mucocutaneous lesions usually begin to appear during the second to third decades of life (average, 22 years; range, birth to 75 years). Facial tricholemmomas present as multiple skin-colored to yellowish-tan, verrucous, or keratotic papules that resemble common warts13 (Fig. 63.3A; see Ch. 111). Both tricholemmomas and nonspecific cutaneous papules show a predilection for the central face, and they may coalesce around facial orifices (especially the nostrils) and on the ears. Papules on the head and neck of CS patients may also represent inverted follicular keratoses or acrochordons.
Multiple sclerotic fibromas of the skin are a relatively specific cutaneous marker of CS14. These lesions present as sharply circumscribed, firm dermal papules that display a strikingly uniform storiform pattern of collagen bundles on histologic examination (see Ch. 116). Punctate palmoplantar keratoses, often translucent with a central depression, are present in more than half of patients15 (Fig. 63.4). Keratotic papules can also be seen on the heels, the dorsal aspects of the hands and feet, and the extensor surfaces of the forearms and lower legs.
Other skin and soft tissue manifestations include lipomas (especially testicular lipomatosis), angiolipomas, and vascular anomalies. The vascular anomalies of CS and BRRS tend to be multifocal, fast-flow lesions with intramuscular involvement and associated ectopic fat16. A distinctive "PTEN hamartoma of soft tissue" that presents as a subcutaneous and intramuscular mass with adipocytic, fibrous, and vascular (arterial, venous) components and sometimes lymphoid, bony, and neural elements has also been described17. Lastly, recent series have suggested that CS patients may have a slightly increased risk of melanoma, with a lifetime incidence of ~5%. Oral lesions of CS appear as 1-3 mm, asymptomatic, mucosa-colored papules that often lead to a cobblestone appearance (Fig. 63.3B). They have a predilection for the lips and tongue, but extensive involvement of the entire oral cavity can occur15

estimated to be 10 to >30%. Fibrocystic disease and fibroadenomas of the breast affect three-quarters of female patients. Breast carcinoma develops in up to 85% of female patients with CS and is diagnosed at a mean age of approximately 40 years7,18; it has also been reported in affected men19.
Multiple polyps may be found anywhere in the gastrointestinal tract but most frequently affect the colon (≥85% of patients). The lifetime risk of colon carcinoma is estimated to be ~10%12,18. Benign ovarian cysts and uterine leiomyomas commonly develop and endometrial carcinoma occurs in as many as 20-30% of women with CS12,18. The lifetime risk of renal carcinoma is estimated to be as high as ~30%
Histologically, tricholemmomas are characterized by a lobular proliferation of pale keratinocytes, often in association with a hair follicle. Basal keratinocytes are oriented to form a palisade, and hyperkeratosis can lead to a cutaneous horn. Demonstration of complete loss of PTEN expression within a tricholemmoma via immunohistochemical staining is suggestive that the patient has CS20. Histologically, some facial papules in patients with CS may simply be squamous papillomas, while others show follicular infundibular hyperplasia. Oral lesions often represent fibromatous nodules with collagen fibers arranged in whorls. On biopsy, extrafacial and palmoplantar papules tend to be hyperkeratotic papillomas, and they may have changes reminiscent of verrucae or acrokeratosis verruciformis21.

Differential Diagnosis
The clinical differential diagnosis of the oral papillomas of CS includes verrucae, focal epithelial hyperplasia (Heck disease), traumatic fibromas, mucosal neuromas of MEN 2B, papillomas of Goltz syndrome, and papular lesions of lipoid proteinosis. A combination of acral keratoses (including palmoplantar) plus oral and facial papules can also be seen in Darier disease, whereas multiple facial angiofibromas and gingival fibromas are characteristic of tuberous sclerosis. These disorders can usually be differentiated from CS by other characteristic features as well as histologic evaluation.
The clinical differential diagnosis of multiple facial tricholemmomas may include angiofibromas (as seen in tuberous sclerosis or MEN 1), trichoepitheliomas, and fibrofolliculomas (Birt-Hogg-Dubé syndrome); in addition to their histologic features, the tendency of tricholemmomas to have a verrucous appearance clinically may help to distinguish them from these lesions. Common warts, seborrheic keratoses, basaloid follicular hamartoma syndrome, and epidermodysplasia verruciformis may represent additional diagnostic possibilities. Less commonly, multiple syringomas or the basal cell nevus syndrome might be considered (see Fig. 111.5).
Germline mutations in the SDHB/C/D genes, which encode subunits of mitochondrial succinate dehydrogenase, have been associated with an autosomal dominant CS-like disorder characterized by a predisposition to the development of breast, thyroid, and renal carcinomas; to date, cutaneous manifestations have not been described22. Predisposition to the same malignancies as well as endometrial carcinoma has been associated with germline epigenetic alteration in the KLLN gene, which encodes a p53-regulated DNA replication inhibitor23. One study found that ~10% of patients with a CS-like disorder but no PTEN or SDHB/C/D mutations had a germline mutation in PIK3CA or AKT124, which encode proteins that activate mTOR signaling (see Fig. 55.3); cutaneous findings such as tricholemmomas and lipomas were noted in a few affected individuals.

Although the recognition of CS and other forms of PHTS is based upon clinical and histologic evaluation, genetic testing can help to confirm the diagnosis and facilitate identification of affected family members. Due to the high risk of malignancy, cancer surveillance is a critical part of PHTS management (see Table 63.3).
Agents that downregulate the mTOR pathway, such as sirolimus (rapamycin), represent promising therapeutic approaches for PHTS that are currently under investigation, with reports of improvement of infiltrative vascular anomalies and lipomatosis following treatment25,26. The facial papules of CS respond variably to topical 5-fluorouracil, oral isotretinoin, curettage, laser ablation, or surgical excision
The main features of Gardner syndrome (GS) are premalignant intestinal polyposis, epidermoid cysts, osteomas, and desmoid or fibrous tumors of the skin and other sites. It is considered to represent a phenotypic variant of the familial adenomatous polyposis syndrome with prominent extraintestinal involvement

In 1953, Gardner and Stephens described a large family in which many individuals had multiple cutaneous lesions, osteomatosis and fatal bowel cancer. The syndrome now bears Gardner's name.

The incidence of GS is approximately 1 in 8000 to 1 in 16 000 births. It is inherited as an autosomal dominant trait with high penetrance and variable expressivity, affecting men and women equally.

GS is caused by heterozygous germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. The APC gene encodes a protein that downregulates the Wnt/β-catenin signaling pathway, which has important functions in cellular proliferation, differentiation and adhesion (see Fig. 55.6).
Cutaneous and soft tissue manifestations
Skin lesions and bony abnormalities appear during childhood and adolescence, frequently preceding the onset of polyposis. Cutaneous epidermoid cysts affect ~30-50% of patients with GS and are often multiple. These lesions are commonly found on the head and neck, may be present at birth, and tend to increase in size and number and then stabilize. Multiple familial pilomatricomas have also been reported as a presentation of GS30.
Desmoid tumors are non-encapsulated, non-metastasizing, locally aggressive benign tumors that occur in 10-20% of patients with GS. There is a marked female predominance (70% to 85%). Desmoid tumors may occur spontaneously or at incision sites, arising from musculo-aponeurotic soft tissues. They commonly develop after colectomy and most often arise within the abdominal wall or intra-abdominally, with the latter causing greater morbidity via obstruction of the small bowel and/or ureters. Extra-abdominal lesions affecting the shoulder girdle, chest wall, or inguinal region can also occur. Although cytologically benign, desmoid tumors can be locally aggressive and may lead to substantial morbidity and even mortality. Hereditary desmoid disease characterized by multiple desmoid tumors, often at unusual sites, in patients with few or no colonic polyps has been described in association with APC mutations31.
Fibromas may occur in the skin, subcutaneous tissues, mesentery, or retroperitoneum. The "Gardner fibroma" often arises in the first decade of life, favors the back and paraspinal region, and can serve as a desmoid precursor. Lipomas, leiomyomas, trichoepitheliomas, neurofibromas, and ovarian cysts are observed less commonly.

Gastrointestinal manifestations
In adults, the diagnosis of GS is commonly made when the patient presents with gastrointestinal bleeding secondary to adenomatous polyps. Other findings may include anemia, abdominal pain, diarrhea or constipation, and weight loss. Premalignant adenomatous polyps most commonly occur in the colon but are also found in the small intestine and stomach in over half of patients. Polyps are typically <1 cm in diameter and are rarely seen before the age of 10 years. By the age of 20 years, 50% of patients with GS have demonstrable polyps. Without surgical intervention, colorectal carcinoma is inevitable; it usually develops before age 40 years and arises by early adolescence in approximately 5% of affected individuals29,34. Carcinomas of the small intestine (especially the duodenum) can also occur
Other extraintestinal manifestations
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is evident in ~75% of patients with GS and can be an early sign of the disorder32 (Fig. 63.5). Because CHRPE is present at birth and easily detected by ophthalmologic examination, it is a useful finding in patients who do not yet have other manifestations. While unilateral solitary CHRPE may occur in unaffected individuals, multiple and bilateral lesions represent a sensitive and specific marker for GS. There are rare reports of adenocarcinoma arising from CHRPE.
Osteomas occur in ~80% of patients and favor the mandible and maxilla, although they can develop in other bones of the skull and in long bones. Seen in children as young as 8 years of age, osteomas are painless and may grow large enough to be clinically obvious or they may be detectable only by radiographic studies. Other skeletal lesions include exostoses, endostoses, and cortical thickening of the long bones. Dental anomalies are seen in ~20% of patients with GS and include supernumerary teeth, odontomas, unerupted teeth, and multiple caries.
Patients with GS are at increased risk for the development of other tumors, including papillary carcinoma of the thyroid (particularly in women), hepatoblastoma (usually affecting children less than 3 years of age), pancreatic and biliary tract carcinomas, adrenal adenomas (or occasionally carcinomas), and various sarcomas (e.g. fibrosarcoma, osteosarcoma). The association of brain tumors (most often medulloblastomas) with adenomatous polyposis in patients with heterozygous APC mutations has historically been referred to as Turcot syndrome type 2. The latter is distinct from the constitutional mismatch repair deficiency syndrome (previously referred to as Turcot syndrome type 1) that presents during childhood with brain tumors (primarily glioblastomas), colonic polyposis, hematologic malignancies, and multiple café-au-lait macules due to biallelic mutations in mismatch repair genes

Histologically, intestinal polyps show adenomatous hyperplasia of the mucosa. Cutaneous cysts in patients with GS usually demonstrate the same microscopic changes as ordinary epidermoid cysts, with a lining of keratinizing epithelium that includes a granular layer. Pilomatricoma-like changes, with characteristic basophilic and shadow cell populations, have also been noted in the cysts of GS.
Genetic counseling is imperative, and family members should be evaluated for extraintestinal and intestinal signs of the disorder. Molecular testing for APC mutations is commercially available. Because of the inevitable development of colorectal carcinoma, prophylactic colectomy is recommended when polyp formation becomes evident, and it is usually performed between 15 and 25 years of age. Initially, children with GS should be monitored with annual flexible sigmoidoscopy or colonoscopy beginning at 10-12 years of age. Once polyps are detected, patients should undergo annual colonoscopy until a colectomy is done. Upper gastrointestinal endoscopy is recommended every 1-3 years (depending on polyp burden), with careful inspection of the ampulla of Vater because of the increased risk of cancer in this area. Barium studies or (preferably) capsule endoscopy can be utilized periodically to evaluate the remainder of the small bowel. Because of the increased risk of hepatoblastoma, some experts recommend annual abdominal ultrasounds and measurement of serum α-fetoprotein levels during the first 5 years of life.
Symptomatic epidermoid cysts can be surgically excised. Desmoid tumors are also treated by surgical excision, although there tends to be a high recurrence rate. Preoperative MRI of the abdomen can demonstrate the origin of the tumor and the extent of involvement. If wide surgical excision fails, radiotherapy, hormonal therapy (e.g. tamoxifen, raloxifene), chemotherapy, or a combination thereof can be tried. The osteomas of GS may or may not be amenable to surgical intervention. Medications that affect prostaglandin metabolism, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may reduce the risk of colorectal cancer and desmoids36
Muir-Torre syndrome (MTS) is an uncommon autosomal dominant genodermatosis that is characterized by sebaceous neoplasms (adenoma, sebaceoma, or carcinoma; see Ch. 111), keratoacanthomas, and internal malignancies. It is considered to represent a subtype of Lynch syndrome, which is also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome37.

Muir in 1967 and Torre in 1968 independently reported the syndrome that bears their names. Their two patients had malignancies in several organs plus either keratoacanthoma-like lesions or multiple tumors of sebaceous origin.

The male : female ratio in MTS is 3 : 2, and affected individuals present with cutaneous manifestations at a mean age of 55 years. The prevalence of Lynch syndrome in the general population is estimated to be ~1 in 500. In a study of Lynch syndrome patients, MTS was observed in 28% (14/50) of families and 9% (14/152) of individuals with a confirmed germline mismatch repair gene mutation38.

MTS is caused by heterozygous germline mutations in one of several DNA mismatch repair genes, including MSH2 (70-90% of MTS cases), MLH1, and MSH639. In patients with MTS, somatic inactivation of the other allele of the affected gene (loss of heterozygosity) results in microsatellite instability, i.e. increased variability in the lengths of repetitive "microsatellite" sequences in the genome, as well as mutations that lead to tumor formation40
More Muir TorreDifferential Diagnosis Sebaceous hyperplasia is a common finding in normal individuals and sebaceous adenomas and carcinomas can occur in patients without MTS. Sebaceous adenomas and carcinomas as well as colorectal carcinomas and other malignancies have been described in patients with autosomal recessive colorectal adenomatous polyposis caused by mutations in the MUTYH base excision repair gene35. Multiple keratoacanthomas may occur as an isolated finding (i.e. without visceral malignancy), especially in patients with the Ferguson-Smith (multiple self-healing) or Grzybowski (generalized eruptive) types of keratoacanthomas. However, these patients should be evaluated to exclude the possibility of MTS. Treatment Patients with an internal malignancy require appropriate oncologic referral and management. Recommendations for surveillance of high-risk individuals are outlined in Table 63.6. Long-term aspirin therapy may decrease the risk of colorectal carcinoma in patients with Lynch syndrome37. Treatment options for the benign sebaceous tumors include curettage, excision, cryosurgery and radiotherapy. Mohs micrographic surgery is recommended for sebaceous carcinomas on the face. Oral retinoids with or without interferon-α may be useful in the prevention of new sebaceous neoplasms.Survallience for Muir Torre• Comprehensive physical examination, including the skin, and neurologic assessment • Age 20-25 years • Yearly • Colonoscopy • Age 20-25 years • If diagnosed in a family member before age 25 years, 2-5 years prior to the earliest colon cancer in the family • Every 1-2 years • Pelvic examination, endometrial biopsy, and transvaginal ultrasound* • Age 30-35 years* • Yearly • Esophagogastroduodenoscopy with biopsy of the gastric antrum and treatment of H. pylori infection when found • Age 30-35 years • Every 2-3 years, based on individual risk factors • Urinalysis ± cytological examination • Age 25-30 years • YearlyAlkaptonuriaAlkaptonuria is an autosomal recessive inborn error of metabolism in which homogentisic acid (HGA), an intermediate in phenylalanine and tyrosine metabolism, cannot be further metabolized and therefore accumulates in body fluids and tissues54. The disorder results from a deficiency of the enzyme homogentisate 1,2-dioxygenase. It is estimated to have a prevalence of ~1 in 250 000 in most ethnic groups, but as high as 1 in 20 000 in Slovakia and the Dominican Republic due to founder effects. The cardinal clinical features of alkaptonuria include urine that turns dark on standing, pigmentation of cartilage and other connective tissues, and arthritis (Fig. 63.8). The arthritis often presents in the third or fourth decade of life with chronic back pain and stiffness, and radiographs show flattened and calcified intervertebral discs. Later involvement of large peripheral joints can resemble rheumatoid arthritis clinically but osteoarthritis radiographically. Renal complications include an increased incidence of calculi and occasionally kidney failure. Aortic stenosis is common by the sixth or seventh decade of life and coronary artery calcifications may also develop55. Life expectancy is normal. The dermatologic features of alkaptonuria are rarely noted prior to 10-15 years of age and typically become apparent during adulthood, often in the fourth decade of life. Axillary skin may be one of the initial sites to develop discoloration, which can range in color from blue to yellow to brown. The classic blue-grey pigmentation associated with this disorder is often first noted in the helices of the ear and sclerae (see Fig. 63.8). Later, it may affect the entire face as well as the palmar and plantar surfaces. Features that may present early in life include brownish discoloration of diapers (due to the dark urine) and cerumen that is brown to black in color. Diagnosis of alkaptonuria can be confirmed by urine organic acid analysis. Management includes physical therapy and pain control as needed. Beginning at age 40 years, periodic cardiac assessment with echocardiography is recommended55. Administration of oral nitisinone, an inhibitor of HGA production, at a dose of 2 mg daily reduces urinary HGA excretion by >95%, although the clinical benefits remain to be determined; a low-protein diet in conjunction with this medication may help to prevent excessively high plasma tyrosine levels54,56Biotinidase deficiency and holocarboxylase synthetase deficiencyBiotinidase deficiency and holocarboxylase synthetase deficiency are genetically distinct autosomal recessive disorders that result in multiple carboxylase deficiency; the former has its onset during infancy or childhood, while the latter presents during the first 3 months of life. Dermatologic features, which overlap with other forms of "nutritional dermatitis" (see Fig. 51.13), occur in >50% of patients with biotinidase deficiency and a smaller proportion of those with holocarboxylase synthetase deficiency57,58. Characteristic skin findings include progressive alopecia and a well-demarcated dermatitis with erythema and scaling that typically begins in perioral, perianal and acral regions, but then can become generalized. This eruption is often eroded or fissured, and superimposed candidiasis may develop. Biotinidase deficiency, a pan-ethnic disorder with an incidence of approximately 1 in 60 000 births, represents a defect in biotin recycling. Patients with this disorder become functionally biotin-deficient under conditions of normal dietary biotin intake. Since biotin is an essential cofactor for the activity of carboxylases, multiple carboxylase deficiency ensues. The clinical manifestations of the disorder, although entirely preventable with the administration of 5-20 mg of biotin daily, are highly variable and may go unrecognized. This has led to the inclusion of biotinidase deficiency in the newborn screening panel of a number of countries, including the US58. Both cutaneous and extracutaneous manifestations usually develop between 3 months and 2 years of age but may be delayed until later childhood. Extracutaneous features include developmental delay, hearing loss, seizures, conjunctivitis, optic atrophy, myelopathy, and metabolic acidosis. Abnormalities on urine organic acid analysis are not consistently present. The diagnosis is established by an assay of biotinidase activity in blood; prenatal diagnosis is possible via enzymatic and molecular analyses. Holocarboxylase synthetase deficiency is significantly less common than biotinidase deficiency. It represents a defect in biotinylation of the apocarboxylases, leading to a failure in synthesis of intact functional holocarboxylases. Patients typically present within the first 3 months of life with symptoms of a metabolic encephalopathy, including poor feeding, lethargy, respiratory distress, and hypotonia. Metabolic acidosis, hyperammonemia, and organic aciduria are often observed. Definitive diagnosis is established by assays of carboxylases in leukocytes or cultured skin fibroblasts; prenatal diagnosis is also possible via enzymatic and molecular analyses. Most patients exhibit significant improvement when treated with 10 mg of biotin daily.Fabry DiseaseFabry disease is an X-linked lysosomal storage disorder resulting from a defect in glycosphingolipid metabolism59. It is a pan-ethnic disorder affecting ~1 in 40 000 men. Female heterozygotes may also be affected, although their clinical manifestations vary and often have a later onset. Fabry disease is caused by mutations in GLA, which encodes the enzyme α-galactosidase A. This leads to systemic deposition of neutral glycosphingolipids, predominantly globotriaosylceramide and galabiosylceramide. The clinical manifestations result primarily from the accumulation of glycosphingolipids within the vascular endothelium of various organs and tissues, which leads to ischemia and infarction. Fabry disease classically presents during childhood or adolescence with the cardinal clinical features of acral pain, acral paresthesias, hypohidrosis, and angiokeratomas (Fig. 63.9). Characteristic whorled corneal opacities ("cornea verticillata") are also evident in ~75% of both male hemizygotes and female heterozygotes by childhood or adolescence; posterior lenticular opacities and tortuous retinal or conjunctival vessels may also be observed. However, these early findings can be subtle or absent in atypical variants of Fabry disease with delayed onset. With increasing age, progressive renal insufficiency develops, leading to the need for dialysis or transplantation by the fourth or fifth decade of life in most male patients. Cardiac sequelae such as hypertrophic cardiomyopathy, arrhythmias, valvular abnormalities, and coronary insufficiency occur in most affected men by middle age and represent the most common cause of premature death in both men and women with Fabry disease. Manifestations in other organ systems can include: transient ischemic attacks and strokes; abdominal pain, diarrhea, and vomiting (especially in children); obstructive lung disease; joint pain and osteopenia; and hearing loss59,60. Characteristic facial features such as periorbital fullness, bushy eyebrows, a broad nasal bridge, thick lips, prognathism, and prominent earlobes have been noted in men with Fabry disease.More Fabry DiseaseAngiokeratomas are one of the earliest signs of Fabry disease, typically beginning to appear during childhood or adolescence61-63. They develop in most male patients and ~30% of female heterozygotes. Angiokeratomas present as punctate, dark-red to blue-black macules or papules (Fig. 63.10). The lesions do not blanch with pressure and may become slightly keratotic as they enlarge. The angiokeratomas of Fabry disease, referred to as angiokeratoma corporis diffusum, tend to be concentrated between the umbilicus and the knees but can develop at any cutaneous site (see Fig. 63.10); oral and conjunctival lesions are also seen. Less frequent vascular findings include linear telangiectasias favoring the face, lips, and oral mucosa; episodic acral vasospasm resembling Raynaud phenomenon, typically accompanied by pain and paresthesias; and peripheral edema and lymphedema62,63. Hypohidrosis is an early and almost constant feature of Fabry disease that can result in heat intolerance. Decreased body hair has also been described. Histologically, angiokeratomas are composed of dilated capillaries in the uppermost dermis, partially enclosed by elongated rete ridges (see Ch. 114); hyperkeratosis may be seen in older lesions. In the skin, there is evidence of lipid storage in endothelial cells, pericytes, arteriolar smooth muscle, and arrector pili muscle. This can be detected by a lipid stain such as Sudan black B, or highlighted by periodic acid Schiff (PAS) staining. Lipid accumulation may also be observed in sweat gland epithelium (see Ch. 39) and perineural cells. Ultrastructural examination demonstrates characteristic cytoplasmic inclusions in all of these cell types. The diagnosis of Fabry disease can be established by demonstration of deficient α-galactosidase A activity in plasma, leukocytes, or cultures of amniocytes or chorionic villi obtained from prenatal testing. However, enzyme activity is within the normal range in up to a third of female heterozygotes. Analysis of the GLA gene is clinically available and can be helpful in: (1) determining disease status in female patients; (2) predicting disease severity in affected male patients; and (3) establishing a prenatal/preimplantation diagnosis. Polarizing microscopy of urine from Fabry disease patients reveals birefringent lipid globules ("Maltese crosses")60 (see Fig. 63.9). Although most commonly seen in association with Fabry disease, angiokeratoma corporis diffusum can also be observed in several other lysosomal storage disorders, as outlined in Table 63.764-70. Scrotal and vulvar angiokeratomas are also commonly found in older adults (see Ch. 114). Enzyme-replacement therapy with recombinant agalsidase-α or β is available (the latter is FDA-approved) and is administered biweekly by intravenous infusion. Accumulated data indicate that it is effective in arresting progression of the disorder, especially when initiated early in the disease process71-73. Current guidelines recommend considering enzyme-replacement therapy in all symptomatic patients, and at 8-10 years of age in asymptomatic boys with classic loss-of-function GLA mutations73. Recent controlled studies found that treatment with migalastat, an oral pharmacologic chaperone that stabilizes specific mutant forms of α-galactosidase, may reduce renal glycosphingolipid accumulation, left ventricular hypertrophy, and gastrointestinal symptoms in Fabry disease patients with suitable mutations73a,73b. Other interventions include gabapentin or carbamazepine for neuropathic pain and angiotensin-converting enzyme inhibitors to reduce proteinuria.Fucosidosis is a rare autosomal recessive lysosomal storage disorder resulting from mutations in FUCA1, which encodes the enzyme α-fucosidase. In the past, patients were classified into two groups: type I, a more severe form with onset in the first year of life; and type II, a milder form with onset in the second year or later67. However, a continuous spectrum of severity is now recognized. The extracutaneous manifestations include coarse facial features, growth retardation, organomegaly, dysostosis multiplex, and neurologic deterioration with associated hypomyelination (see Fig. 63.9). Patients may also have corneal opacities, retinal vascular abnormalities, and frequent sinopulmonary infections. Angiokeratomas virtually indistinguishable from those associated with Fabry disease are found in approximately one-third of fucosidosis patients <10 years of age and 85% of those 10-19 years of age. The lesions are distributed primarily on the trunk and lower extremities but can also develop within the mouth. Other reported cutaneous findings include telangiectasias, acrocyanosis, nevus anemicus, xerosis, and elevated sweat chloride levels74. The light microscopy findings of the angiokeratomas are similar to those seen in Fabry disease. Electron microscopic examination of clinically normal skin may reveal empty-appearing storage vesicles in endothelial cells, melanocytes, eccrine glands, and fibroblasts. The diagnosis of fucosidosis is supported by demonstration of characteristic abnormalities on urine oligosaccharide analysis and established by an α-fucosidase assay utilizing leukocytes or cultured skin fibroblasts. Prenatal diagnosis is possible via enzyme analysis or genetic testing. There is no definitive treatment for fucosidosis, and the mortality rate is high, especially after the second decade of life. Bone marrow transplantation has been attempted with some evidence of clinical improvementGaucher DiseaseGaucher disease is a relatively common autosomal recessive lysosomal storage disorder in which the glycolipid glucocerebroside accumulates as a result of a deficiency of the enzyme glucocerebrosidase (β-glucosidase). There are three clinical subtypes of the disorder, although the acute and chronic neuronopathic forms (types 2 and 3, respectively) are thought to exist on a continuum. Type 1 is by far the most common form of Gaucher disease and has a particularly high incidence of ~1 in 850 births in the Ashkenazi Jewish population. Type 1 Gaucher disease is distinguished by a lack of primary involvement of the CNS, although Parkinson disease-like symptoms develop by the eighth decade of life in ~10% of affected individuals. Presenting findings in type 1 may include hepatosplenomegaly, thrombocytopenia, anemia, and bone pain. The cutaneous manifestations of type 1 Gaucher disease are infrequent and relatively nonspecific76. They include diffuse brown or yellow-brown pigmentation of the skin and easy tanning. In addition, petechiae and ecchymoses may be observed due to the thrombocytopenia that results from infiltration of the bone marrow with glycolipid-filled macrophages (Gaucher cells) or from hypersplenism. Type 2 Gaucher disease, the acute neuronopathic form of the disorder, is a severe and rapidly progressive condition that usually results in death before 2 years of age. Clinical manifestations develop within the first year of life and include hepatosplenomegaly, severe hypertonia, opisthotonus, oculomotor apraxia, and progressive neurologic deterioration. A subgroup of patients with this type of Gaucher disease presents at birth with a collodion baby phenotype or other ichthyosiform skin findings77,78, suggesting that Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis. Studies in a mouse model indicate that glucocerebrosidase is required to generate functionally competent membranes for normal epidermal barrier function. Electron microscopy of skin samples from patients with type 2 Gaucher disease, including those without clinically evident ichthyosis, shows immature lamellar membranes with characteristic electron-dense clefts79. The residual enzymatic activity present in patients with types 1 and 3 Gaucher disease is apparently adequate to protect them, since similar epidermal abnormalities are not observed in these forms. In fact, no specific cutaneous abnormalities have been described in patients with type 3 (chronic neuronopathic) Gaucher disease. The diagnosis of Gaucher disease is established by demonstration of a glucocerebrosidase deficiency in leukocytes or cultured skin fibroblasts. Carrier detection is possible by genetic analysis, and prenatal diagnosis can be accomplished via chorionic villus sampling (CVS) or amniocentesis. The treatment of symptomatic patients with type 1 Gaucher disease involves intravenous enzyme-replacement therapy using a recombinant product. This results in arrest of the progression of the disorder, gradual resolution of organomegaly, and some improvement in bone disease80. Substrate-reduction therapy with eliglustat or miglustat, inhibitors of glucosylceramide synthase, can also lead to clinical improvement81. However, these treatments have minimal impact on ameliorating the CNS manifestations of Gaucher disease. Hematopoietic stem cell transplantation may be of potential benefit in type 3 patients.Hartnup diseaseHartnup disease is an autosomal recessive disorder caused by mutations in SLC6A19, which encodes a transporter that mediates epithelial uptake of neutral amino acids in the kidneys and intestines82. The hallmark of the disorder is a specific hyperaminoaciduria due to diminished renal reabsorption of neutral amino acids. In most affected individuals, there is also reduced intestinal absorption of at least some neutral amino acids, most notably tryptophan. Hartnup disease is one of the most common amino acid disorders, occurring in about 1 in 30 000 births. Most affected individuals, particularly those in high-income countries, remain asymptomatic throughout life, although symptoms can occur when exacerbating factors such as poor nutrition, celiac disease, or other causes of persistent diarrhea are present. When clinical features develop, the most common finding is a photosensitive "pellagra-like" dermatosis83. This eruption may be related to a relative niacin deficiency, as tryptophan is a precursor in niacin synthesis. It typically develops in patients <13 years of age on exposed areas of the body and may initially resemble a sunburn or acute cutaneous lupus erythematosus. After the development of erythema following sun exposure, the affected skin becomes dry and scaly with well-defined margins; later findings include desquamation and hypo- or hyperpigmentation. The dermatosis is occasionally pruritic and blistering may occur; acrodermatitis enteropathica- and hydroa vacciniforme-like presentations have been described83. The second major manifestation of symptomatic Hartnup disease is intermittent ataxia, which may be accompanied by nystagmus and tremors. Psychiatric disturbances, developmental delay, and other neurologic abnormalities have been reported in some patients. The diagnosis of Hartnup disease is established by urine amino acid analysis, which reveals markedly elevated levels of neutral amino acids. In contrast, plasma levels of amino acids and niacin are typically normal, despite the clinical resemblance to pellagra. Nonetheless, dermatologic and neurologic manifestations often respond to administration of oral nicotinamide in doses of 50-300 mg/day. A high-protein diet or protein supplementation may also be beneficial in some patients.Mitochondrial disordersMitochondrial disorders represent a clinically and biochemically heterogeneous group of metabolic conditions characterized by impairment of the mitochondrial respiratory chain, which generates most of the adenosine triphosphate (ATP) required for cellular functioning84. The mitochondrial genome contains 37 genes and they encode subunits of the respiratory chain as well as the transfer and ribosomal RNAs (tRNAs and rRNAs) that translate mitochondrial DNA (mtDNA). However, some of the genes that encode respiratory chain components and other mitochondrial proteins are encoded by nuclear DNA. Mitochondrial disorders can therefore result from either maternal inheritance of mtDNA mutations or Mendelian inheritance of nuclear DNA mutations. The respiratory chain is organized into five enzyme complexes (I-V), the activity of which can be measured in muscle or other tissues to aid in the diagnosis of mitochondrial disorders. Although some mitochondrial syndromes are characterized by a particular constellation of clinical findings, there is often poor correlation between the enzyme complex involved and the clinical phenotype. Mitochondrial disorders can present at any age and may potentially affect any organ system, but with a predilection for cells with high energy requirements such as neurons and muscle84. Common manifestations include developmental delay, seizures, stroke, weakness, hypotonia, and cardiomyopathy. Visual impairment, hearing loss, proximal renal tubular defects, hepatic dysfunction, poor growth, and fatigue are other frequent findings. The clinical course and progression are highly variable, even in patients with similar biochemical abnormalities85. A wide range of hair and skin abnormalities has been described in association with mitochondrial disorders (Table 63.8)86. These manifestations have been reported in about 5-10% of patients with documented mitochondrial disorders and may develop early in the disease course. When such findings are noted in conjunction with seemingly unrelated abnormalities in other organ systems, the possibility of a mitochondrial disorder should be considered. Biochemical and/or molecular genetic confirmation of the diagnosis of a mitochondrial disorder is rarely straightforward. Measurement of plasma lactate, plasma amino acids, and urine organic acids can be helpful in assessing mitochondrial function. Other components of the evaluation may include exercise testing, neuroimaging, muscle biopsy for histologic/histochemical evaluation, assays of respiratory chain enzyme complexes in muscle tissue or cultured skin fibroblasts, and genetic analysis84. Treatment of patients with mitochondrial disorders is largely symptomatic. A variety of dietary modifications have been tried and may be helpful for some patients. Coenzyme Q10, L-carnitine, resveratrol, curcumin, sulforaphane, and riboflavin supplementation are commonly used and may have some benefit.Niemann pick diseaseNiemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency, which results in the accumulation of sphingomyelin and other phospholipids87. There are two classic forms: type A, with an incidence of 1 in 40 000 births in the Ashkenazi Jewish population; and type B, with a lower incidence and no specific ethnic predilection. Type A is a severe disorder associated with failure to thrive, hepatosplenomegaly, and rapid neurologic degeneration leading to death by 2-3 years of age; cherry-red retinal spots are evident in ~50% of patients. Type B is characterized by little or no neurologic involvement, later onset, and survival into adult life. Progressive pulmonary infiltration may occur in either subtype. Niemann-Pick type C is associated with an accumulation of unesterified cholesterol and underlying mutations in different genes; it has primarily neurologic manifestations and will not be discussed further. Cutaneous manifestations are typically observed only in patients with Niemann-Pick disease type A. The skin may exhibit a generalized ochre or brownish-yellow discoloration. Papular lesions, most commonly located on the face and upper extremities, may also be present. Histologically, the papules of Niemann-Pick disease consist of foamy histiocytes, multinucleated cells, and a variable infiltrate of lymphocytes. Diagnosis of Niemann-Pick disease type A or B is established by demonstration of deficient sphingomyelinase activity in leukocytes or cultured skin fibroblasts. Carrier detection for type A can be performed via genetic testing, and prenatal diagnosis is available by CVS or amniocentesis. Enzyme-replacement therapy is being investigated for type B disease, and hematopoietic stem cell transplantation may have some benefit, especially for non-neurologic manifestations87PhenylketonuriaPhenylketonuria (PKU) is one of the most common inborn errors of metabolism, occurring worldwide with an incidence of ~1 in 10 000 births. It is an autosomal recessive disorder resulting from a deficiency of the enzyme phenylalanine hydroxylase that is responsible for conversion of phenylalanine to tyrosine. As a result of this enzyme deficiency, phenylalanine levels rise in blood and tissues of the untreated patient on a phenylalanine-containing diet, and high levels of this amino acid are extremely toxic to the CNS. Progressive developmental delay, ultimately leading to mental retardation, occurs and may be accompanied by seizures, behavioral problems, and psychiatric symptoms88. In patients with PKU, a relative deficiency of tyrosine and/or competitive inhibition of tyrosinase by excess L-phenylalanine leads to diminished melanin production and resultant diffuse pigmentary dilution. The classic patient is described as blond and blue-eyed, although pigmentation varies depending on the family and ethnic background. Sweat with a musty or "mousy" odor can represent a clue to the diagnosis. Nonspecific dermatitis occurs with increased frequency, and early-onset atopic dermatitis affects up to half of patients with PKU. Progressive scleroderma-like skin changes that favor the proximal extremities may also be observed, often with an onset in the first year of life89 (Fig. 63.11). This is in contrast to the acral predilection and older age of onset in systemic sclerosis. Newborn screening for PKU is routinely performed in many countries, and the diagnosis is established by plasma amino acid analysis. Identification of affected infants at birth with early institution of a phenylalanine-restricted diet and careful control of blood phenylalanine levels prevents the development of mental retardation and skin changes, although subtle neurocognitive consequences may be observed. Unfortunately, untreated patients are still encountered among children from low-income countries, and despite recommendations that dietary therapy be continued for life, some adolescents and adults do not adhere to the dietary restrictions. In such instances, dermatologic manifestations may develop. In patients who resume treatment in later childhood or adult life, the hair color often darkens and sclerodermatous changes may regress. Dietary therapy involves not only restriction of phenylalanine, but also special medical foods containing phenylalanine-free protein substitutes. Supplementation with tetrabiopterin/sapropterin, large neutral amino acids, and long-chain polyunsaturated fatty acids may also be of benefit. Close monitoring by an experienced nutritionist is vital.Hutchinson gilford progeriaIntroduction Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease characterized by accelerated aging that begins during infancy90,91. The term "progeria" originates from the Greek word for old age, "geras", and was proposed by Gilford when he delineated the clinical features and course of the disorder in 1904. History The syndrome was first reported in 1886 by Jonathan Hutchinson, with Hastings Gilford subsequently documenting the postmortem features. In 2003, mutations in the gene that encodes lamin A were first described91,92. Epidemiology DeBusk90 estimated that HGPS occurred in 1 in 8 million births, and an incidence of 1 in 4 million was observed in the Netherlands from 1900 to 200593. The male : female ratio is 1.2 : 193, and it has been reported worldwide in patients with a wide variety of ethnic backgrounds. In the 64 cases reviewed by DeBusk90, median and mean paternal ages were advanced, consanguinity was uncommon, and the abortion rate in affected families was normal. These observations favored a de novo dominant mutation, which was later confirmed by genetic studies (see below). Since HGPS patients usually do not become sexually mature and typically succumb to the disease early in the second decade of life, familial occurrence is rare; however, it can occur in the setting of gonadal mosaicism93. Consanguineous families with autosomal recessive variants of HGPS have been described, but additional clinical features such as clavicular aplasia/hypoplasia in affected individuals suggest an overlap with mandibuloacral dysplasia, which is caused by biallelic mutations in LMNAMore ProgeriaClinical Features Although affected children usually appear normal at birth, growth failure and other clinical features typically appear rather abruptly during the first year of life90,92,93,101. Weight gain is very slow, with marked loss during episodes of illness. Linear growth proceeds at half the normal pace and does not undergo the normal acceleration around puberty. Sexual maturation is absent in most patients, and affected individuals have both short stature and a low weight for height. Following the onset of growth failure, the skin becomes thin and dry, with less hair than normal. Some areas may appear taut and shiny, whereas others (especially the fingers and toes) lax and wrinkled. At birth or during early infancy, some patients have thick, inelastic, scleroderma-like skin, usually on the lower abdomen, flanks, thighs, and buttocks. Infantile fat is rapidly lost with the onset of growth failure, resulting in prominent superficial veins and the appearance of perioral cyanosis. As the aged appearance progresses, irregular brown pigmentation becomes evident in sun-exposed areas. At the onset of growth failure, patients begin to develop characteristic facial features, including a disproportionately large cranium, frontal bossing, a large open anterior fontanelle, pronounced scalp veins, prominent eyes due to relatively slow growth of the facial bones, a thin beaked nose with a sculpted appearance, and micrognathia. The facial stigmata tend to become marked by age 2 to 3 years, giving a "plucked-bird" appearance. Alopecia develops during the first year of life and becomes diffuse and generalized, with later hair growth tending to be fine and lightly pigmented. Eyebrows and eyelashes are often sparse or absent. Although the nails may be normal, dystrophy in the form of small, short and thin nails is common. Marked delay in the eruption of primary and secondary dentition has also been noted in most patients. Teeth may be crowded, rotated, overlapped and maloccluded, and the voice tends to be high-pitched and piping. Truncal features include a narrow pyriform thorax, shoulders with thin and short clavicles, and prominent thoracic kyphosis giving a stooped appearance. Prominence of the abdomen (relative to the chest) and hypoplastic nipples also contribute to the distinctive habitus. The limbs are usually proportionate and become progressively thinner with increasing prominence of the joints, especially the knees, elbows, and small joints of the hand. Coxa valga is usually present by age 2 to 3 years and, in combination with increasing joint stiffness, contributes to a wide-based gait. Patients are of normal intelligence and may be self-conscious about their appearance. Early onset of progressive coronary and cerebral atherosclerosis results in a median lifespan of 14 years102. Other complications include osteopenia, low-frequency conductive hearing loss, corneal dryness, and hyperopia92. Although mild insulin resistance occurs in up to half of patients, overt diabetes mellitus is rare.More ProgeriaPathology and Laboratory Findings Cutaneous histopathology varies with the site and the age of the patient, and it is usually not helpful in diagnosing the condition103,104. The epidermis is fairly normal with minimal hyperkeratosis and a slight increase in melanin in the basal cell layer. Although dermal elastic tissue is normal, dermal collagen tends to be thickened and hyalinized. Adnexal structures are normal or decreased in density and arrector pili muscles are usually prominent. Radiographic findings include hypoplasia of the facial bones, thinned cranial bones, open fontanelles, and hypoplasia of the mandible with crowding of the teeth. Progressive resorption of bone from the distal phalanges of the fingers and toes is also characteristic, but not diagnostic, of HGPS. Differential Diagnosis The differential diagnosis is outlined in Table 63.9 and includes Werner syndrome, "atypical Werner syndrome", Néstor-Guillermo progeria syndrome, metageria, and acrogeria105. In contrast to HGPS, patients with Werner syndrome have premature canities, cataracts and an increased incidence of malignancy. HGPS should also be distinguished from the following disorders: Cockayne syndrome (Ch. 87), Rothmund-Thomson syndrome (Ch. 87), ataxia-telangiectasia (Ch. 60), Kindler syndrome (Ch. 32), Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), and forms of Ehlers-Danlos syndrome and cutis laxa with progeroid features (Ch. 97). Lastly, clinical overlap may be seen with other disorders that are due to mutations in the LMNA gene, such as early-onset myopathy with progeroid features, restrictive dermopathy (Ch. 34), and mandibuloacral dysplasia (see Table 63.10). Treatment Management is directed toward the prevention and treatment of complications, particularly cardiovascular, cerebrovascular, and musculoskeletal. No dietary regimen has been shown to alter the disease course. Although growth impairment in HGPS is not typically related to growth hormone deficiency, administration of exogenous growth hormone may increase weight and, to a lesser degree, height. Physical and occupational therapy can help to maintain joint mobility, and patients and families may benefit from psychological and genetic counseling. Because farnesylation of the dominant-mutant progerin form of prelamin A causes it to be anchored to the nuclear membrane, thereby disrupting nuclear structure (see Fig. 63.13), inhibitors of farnesylation were identified as a potential treatment for HGPS. Initial studies found that administration of farnesyltransferase inhibitors (FTIs) restored normal nuclear morphology to human HGPS fibroblasts in vitro, and these inhibitors improved body weight, bone density, strength, and survival in mouse models of progeria97,106. Additional investigation in mouse models showed benefit from treatment with the combination of a bisphosphonate and statin, which inhibit farnesyl pyrophosphate synthase and HMG-CoA reductase, respectively. Each of these enzymes functions in the protein prenylation pathway essential to both farnesylation and the alternative pathogenic geranylgeranylation that occurs in the setting of FTI monotherapy. Treatment of HGPS patients with the FTI lonafarnib, either alone or together with the bisphosphonate zoledronate and pravastatin, has been shown to result in small but significant increases in survival102,107. Other possible therapies being explored in preclinical studies include aminopyrimidines that modulate farnesylation, antisense oligonucleotides to reduce progerin production, rapamycin to increase autophagic degradation of progerin, inhibition of isoprenylcysteine carboxyl methyltransferase to mislocalize progerin away from the nuclear rim, resveratrol to restore sirtuin-1 deacetylase activity and prevent stem cell depletion, vitamin D to potentially reduce progerin production, and remodulin to inhibit N-acetyltransferase-10 and rescue nuclear shapeWerner SyndromeIntroduction Werner syndrome is a genetic disorder of accelerated aging with an onset in the second decade of life. This rare progeroid syndrome has a higher incidence in certain populations in Japan110-114. Although it is often referred to as progeria of the adult, Werner syndrome has some distinctive clinical findings not normally associated with aging, such as hypogonadism, laryngeal atrophy, and osteosclerosis of the distal extremities110-113. The discovery of underlying mutations in the RECQL2 (WRN) gene has allowed investigation into the molecular aspects of Werner syndrome111. History In 1904, Otto Werner described a family with two brothers and two sisters between the ages 36 and 40 years who displayed clini cal features of premature aging. In 1934, Oppenheimer and Kugel reported two similar cases and established the eponym Werner syndrome. Epidemiology Werner syndrome is a rare autosomal recessive disorder with an overall incidence of 1 in 1 million births. However, its incidence in Japan is higher and may approach 1 in 3500 in some communities owing to high rates of consanguinity. It was the study of several large Japanese families that led to identification of the gene responsible for this disorder113. Werner syndrome has been reported in all races and affects both sexes equally. Pathogenesis Werner syndrome is caused by mutations in the RECQL2 (WRN) gene, which encodes a homolog of the Escherichia coli RecQ DNA helicase. Almost all of the mutations identified to date predict a truncated protein, and over half of Japanese patients are homozygous for a specific splice-site mutation111. The Werner protein (WRN) has both exonuclease and helicase activities, and it plays a role both in optimizing DNA repair, particularly via base excision, and in suppressing illegitimate recombination. Therefore, loss of RecQ helicase results in genomic instability. The accumulation of senescent cells with decreasing replicative capacity and an increasing number of mutations is thought to lead to the clinical findings of premature aging and an increased risk of malignancy. Decreased heterochromatin stability is also thought to play a role in the accelerated cellular senescence of Werner syndrome as well as physiologic aging115. Loss of function of the RECQL2 gene may occur in the normal population as a function of age111. A subset of patients have "atypical Werner syndrome" and lack pathogenic changes in the RECQL2 gene. Rather, they have heterozygous missense mutations in the LMNA gene (see HGPS section) that affect the heptad repeat region and are predicted to interfere with protein- protein interactions116. Compared to patients with RECQL2 mutations, those with atypical Werner syndrome tend to have an earlier onset of disease and more severe age-related manifestations. Atypical Werner syndrome might therefore be better classified as a late-onset form of HGPS.Werner SyndromeClinical Features In most affected individuals, growth progresses normally until the beginning of the second decade, when short stature and thin limbs become noticeable. Graying of the hair may first appear during childhood but characteristically develops in late adolescence or the early twenties. Other findings of Werner syndrome become evident during the second and third decades of life110-113. The typical patient is short, with an average height of 5 ft (1.5 m), and has spindly limbs but central obesity. The hands and feet are small, and the face is thin with a pinched appearance, prominent eyes, a beaked nose, circumoral radial furrows, taut lips, protuberant teeth and micrognathia (Fig. 63.14). The voice is high-pitched and raspy. Cutaneous changes include atrophy (epidermal, dermal and subcutaneous), scale, mottled hyperpigmentation and tightness reminiscent of scleroderma. These findings are most prominent on the face, forearms, hands, legs and feet. Nails may be dystrophic, hypoplastic or absent, and plantar hyperkeratosis is common. Thick keratoses develop over pressure points such as the fingers, toes, ankles, elbows and, occasionally, the ears. Removal of these keratoses by accidental or deliberate trauma leaves painful progressive ulcers. Ulcers may be resistant to therapy and prone to infection because of ischemia related to peripheral vascular disease. Dystrophic soft tissue calcification and osteomyelitis can also complicate chronic ulcers. Other characteristic findings in Werner syndrome that reflect accelerated aging include bilateral cataracts, type 2 diabetes mellitus, hyperlipidemia, generalized atherosclerosis and osteoporosis. Additional features not normally associated with aging include hypogonadism, laryngeal atrophy, and osteosclerosis of the extremities. Affected individuals have an increased risk of meningiomas, soft tissue sarcomas, and osteosarcoma. Japanese patients are also at increased risk for thyroid carcinomas and melanomas, especially in acral and mucosal locations114. The average lifespan is approximately 50 years, and death is usually related to cardiovascular and cerebrovascular disease. Some authors have postulated that heterozygous carriers may have higher rates of malignancy and myocardial infarction than the general population111,112. Pathology and Laboratory Findings The epidermis is hyperkeratotic and atrophic, with focal hypermelanosis of the basal layer. Appendages are decreased in number and atrophic, and there is fibrosis and variable hyalinization of the dermis. The fat is also atrophic and often replaced by hyalinized connective tissue. Vessels may show changes typical of diabetic angiopathy. Differential Diagnosis A clinical diagnosis can usually be made when the characteristic premature canities, dysmorphic facies, skin findings, and body habitus are recognized. However, there is considerable overlap with the recently described mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by mutations in the POLD1 gene encoding DNA polymerase δ (see Table 63.9)117, which interacts with the Werner helicase during DNA replication and repair. However, MDPL is differentiated by frequent hearing impairment, absence of cataracts, and no predisposition to malignancy. In addition to other premature aging syndromes outlined in Table 63.9, Werner syndrome must be distinguished from ataxia-telangiectasia (see Ch. 60), prolidase deficiency (which features facial dysmorphism, telangiectasias, recalcitrant leg ulcers, and premature canities), and disorders associated with plantar keratoderma and scleroderma-like skin changes, such as Huriez syndrome (see Ch. 58). Treatment Genetic counseling should be provided, and prenatal diagnosis can be offered to affected families. Skin ulcers may prove resistant to therapy and should be treated aggressively and early, with skin grafting occasionally necessary. Case reports have suggested that etidronate may ameliorate painful soft tissue calcifications. Management of diabetes mellitus and hyperlipidemia with proper diet and appropriate medications (e.g. pioglitazone, sitagliptin, lipid-lowering agents) can help to reduce complications, including atherosclerosis. Vitamin C supplementation was found to reverse age-related metabolic abnormalities and increase the lifespan in a mouse model of Werner syndrome, suggesting that vitamin C might be beneficial for Werner syndrome patients1Ectodermal DysplasiasEctodermal dysplasias have long been recognized as a distinct group of inherited disorders that affect ectodermal appendages. Early descriptions of affected individuals were made by Danz in 1792, Wedderburn in 1838, and Darwin in 1875. The term "hereditary ectodermal dysplasia" was subsequently introduced by Weech in 1929. Currently, over 180 single-gene disorders qualify as ectodermal dysplasias by having abnormalities in two or more of the major ectodermal structures - hair, teeth, nails, and sweat glands; other ectodermal structures, such as sebaceous and mucous glands, can also be affected119,120. Some of the conditions included in this group have not been traditionally thought of as ectodermal dysplasias because they are recognized and diagnosed based upon another primary manifestation such as keratoderma, ichthyosis, aplasia cutis congenita, or skeletal dysplasia. It has been suggested that defects in ectodermal appendages should be the major clinical features used to classify and diagnose ectodermal dysplasias. There have been many classification schemes proposed over the years, including a descriptive clinical categorization by Pinheiro and Freire-Maia121, a clinical-genetic model by Priolo and Lagana122, and a functional classification by Lamartine123. Over the past two decades, the molecular basis of many ectodermal dysplasias has been elucidated, and we are beginning to understand the processes of cell signaling involved in the induction and development of ectodermal structures as well as their interactions with mesodermal structures119,124. International conferences were held in 2008 and 2012 with the aim of developing a classification system for ectodermal dysplasias that integrates clinical, genetic, and functional/pathway-based data and is fluid enough to incorporate new discoveries125,126. Tables 63.11, 63.12 and 63.13 summarize the key clinical and genetic features of ectodermal dysplasias with a known molecular basis and/or prominent cutaneous manifestations. Selected classic ectodermal dysplasias are discussed in detail in this chapter.Hypohidrotic ectodermal dysplasiaHypohidrotic ectodermal dysplasia (HED) refers to a group of disorders that share the following features: sparse or absent hair; missing or peg-shaped teeth; and decreased ability to sweat. The most common form is X-linked, and traditionally the term HED has referred to this condition. However, clinically similar conditions with autosomal dominant and autosomal recessive inheritance can result from molecular defects that affect the same pathway as in X-linked HED. Epidemiology The X-linked form of HED is estimated to affect 0.5-2 in 10 000 live-born boys and occurs in all racial and ethnic groups. The autosomal dominant and recessive forms are much less common. Pathogenesis HED is caused by mutations in genes that affect the ectodysplasin signal transduction pathway127 (Fig. 63.15). Epithelial cells in the developing tooth, hair follicle and eccrine gland utilize this pathway during morphogenesis, and errors in signaling result in aplasia, hypoplasia or dysplasia of these structures. Activation of the ectodysplasin pathway at a critical time during development leads to translocation of the NF-κB transcription factor into the nucleus of these epithelial cells, thereby altering the expression of a variety of target genes. The change in gene expression likely has an effect on both cellular proliferation and survival128. The gene that is altered in the X-linked form of HED (EDA) codes for a soluble ligand, ectodysplasin A. It is secreted by a subset of epithelial cells and binds to its receptor (ectodysplasin-A receptor; EDAR) on another group of epithelial cells. Mutations in EDAR cause either autosomal recessive or autosomal dominant HED129. Autosomal recessive and autosomal dominant HED can also be caused by mutations in the EDARADD (EDAR-associated death domain) gene, which encodes an intracellular adapter protein that assists in transducing the signal from the activated receptor to the nucleus130. Molecular analysis of the EDA, EDAR, and EDARADD genes is available in commercial laboratories.Hipohidrotic ectodermal dysplasiaClinical Features Affected newborns may present with a collodion-like membrane or with marked skin scaling. Scalp hair is sparse to absent (Fig. 63.16), and, when present, is usually lightly pigmented. Hair may darken at puberty and secondary sexual hairs are typically normal, although body hair is usually sparse or absent. Most male patients are unable to sweat to a detectable degree131. This can lead to elevation of the core temperature in warm environments or with exertion, and symptomatic hyperthermia is a major problem. Affected infants often present with fever of unknown origin, and hyperthermia during the first few years of life can be fatal when HED is not recognized131,132. The skin is smooth and dermatoglyphics may be effaced because of absent eccrine pores. Atopy is a major cause of morbidity, with eczema affecting nearly two-thirds of HED patients. Periorbital wrinkling and hyperpigmentation are common. Sebaceous hyperplasia of the face, clinically resembling milia, can develop over time (see Fig. 63.16D). The nails are usually normal. Both the primary and secondary dentition are affected. Teeth may be absent or reduced in number and abnormally shaped (e.g. peg-shaped). Affected individuals typically have an alteration in their facial appearance characterized by a saddle nose, full everted lips and frontal bossing (see Fig. 63.16). Nasal secretions and cerumen are thick and viscous, and recurrent respiratory tract infections are common. The voice is frequently hoarse or raspy. Affected infants often develop gastroesophageal reflux and feeding problems. Unilateral or bilateral amastia is an occasional feature. Female patients with the X-linked form of HED fall into one of three categories: (1) carriers with no detectable clinical features; (2) limited involvement with findings such as decreased hair density, one or more peg-shaped or missing teeth, patchy distribution of sweat glands along the lines of Blaschko, and relative hyperpigmentation of the skin that lacks adnexa (most evident on the back); or (3) full-blown features of the disorder (Fig. 63.17). This variability results from the random nature of X-inactivation (see Ch. 62). Pathology A skin biopsy is usually not necessary, but a scalp or palmar biopsy specimen lacking eccrine structures is considered diagnostic of HED133. Microscopic examination of hairs often shows small or variable shaft diameters and parallel dark bands of various lengths resembling a "bar code"134. Differential Diagnosis The majority of affected individuals, either male or female, have the X-linked form. In sporadic cases, molecular diagnosis may be helpful. Homozygous or compound heterozygous mutations in the WNT10A gene can give rise to an HED phenotype without associated facial dysmorphism, in addition to causing odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome135 (see Table 63.13 and Fig. 55.6). Heterozygous WNT10A mutations also represent a common etiology of mild HED or isolated hypodontia. At birth, HED can be confused with an ichthyosis if a collodion-like membrane is present (see Ch. 57, Table 57.3). Recurrent fevers in an infant may lead to consideration of infectious diseases before the features of HED are recognized. HED with immune deficiency (HED-ID) due to mutations in the IKBKG (NEMO) gene can be differentiated by the clinical and laboratory features of the associated immune system abnormalities (see below).HEDTreatment Controlling ambient temperatures and external methods of cooling, e.g. wet T-shirts, wet headbands and cooling vests, are critical to prevent hyperthermia in children with HED. Regular use of moisturizers is helpful for dry skin. Dentures can be fitted in children as young as 3 years of age, and dental restoration through implants should be employed for older patients. Multidisciplinary care is often required for treatment of other manifestations, which range from nasal concretions, asthma and recurrent respiratory infections to weight deficits and reduced salivary secretion. Referral to the National Foundation for Ectodermal Dysplasias (www.nfed.org) is also an important aspect of care. This organization provides information and support to affected families, including yearly regional and national conferences. The potential for protein therapy for HED is on the horizon136,137. In Tabby mice (the murine form of X-linked HED), the administration of recombinant EDA protein in utero or in the immediate postnatal period can completely or partially correct the phenotype138. Neonatal administration of recombinant EDA in a canine model of X-linked HED has also led to significant correction of ectodermal defects139,140. The first human studies of recombinant EDA therapy for neonates and children with X-linked HED were recently initiated137HED-IDHED-ID is a rare condition that shares many features with classic HED but is differentiated by the associated immune abnormalities (see also Ch. 60). Pathogenesis HED-ID is most commonly inherited in an X-linked recessive pattern due to hypomorphic mutations in IKBKG (inhibitor of κ light polypeptide gene enhancer in B cells, kinase γ), which is also known as NEMO (nuclear factor-κB essential modulator). This gene encodes a subunit of a regulatory kinase that activates NF-κB downstream in the ectodysplasin (see Fig. 63.15) and tumor necrosis factor-α (TNF-α) pathways141. The condition primarily affects boys and is allelic to incontinentia pigmenti, which is caused by more detrimental IKBKG mutations that are lethal in male embryos unless in a mosaic state (see Ch. 62). Patients with HED-ID have a high frequency of somatic mosaicism in their T cells, reflecting revertant mutations that are critical for survival in this cell type. An autosomal dominant form of HED-ID due to mutations in the NFKBIA gene has also been described. These patients have decreased NF-κB signaling because the mutated α-component of the NF-κB inhibitor is resistant to degradation (see Fig. 63.15). Clinical Features Individuals with HED-ID often have milder abnormalities of ectodermal structures than do patients with classic HED. The findings can include hypodontia, conical teeth, hypotrichosis, and a reduced ability to sweat; frontal bossing, periorbital wrinkling, and everted lips may also be seen. A seborrheic- or atopic-like dermatitis that evolves into erythroderma may serve as a clue to the diagnosis142, and reticulated hyperpigmentation is occasionally observed. Extracutaneous inflammatory manifestations can include colitis, which affects ~25% of patients, and chronic arthritis.Hypohydrotic ectodermal dysplasia with immune deficiencyHED-ID is a rare condition that shares many features with classic HED but is differentiated by the associated immune abnormalities (see also Ch. 60). Pathogenesis HED-ID is most commonly inherited in an X-linked recessive pattern due to hypomorphic mutations in IKBKG (inhibitor of κ light polypeptide gene enhancer in B cells, kinase γ), which is also known as NEMO (nuclear factor-κB essential modulator). This gene encodes a subunit of a regulatory kinase that activates NF-κB downstream in the ectodysplasin (see Fig. 63.15) and tumor necrosis factor-α (TNF-α) pathways141. The condition primarily affects boys and is allelic to incontinentia pigmenti, which is caused by more detrimental IKBKG mutations that are lethal in male embryos unless in a mosaic state (see Ch. 62). Patients with HED-ID have a high frequency of somatic mosaicism in their T cells, reflecting revertant mutations that are critical for survival in this cell type. An autosomal dominant form of HED-ID due to mutations in the NFKBIA gene has also been described. These patients have decreased NF-κB signaling because the mutated α-component of the NF-κB inhibitor is resistant to degradation (see Fig. 63.15). Clinical Features Individuals with HED-ID often have milder abnormalities of ectodermal structures than do patients with classic HED. The findings can include hypodontia, conical teeth, hypotrichosis, and a reduced ability to sweat; frontal bossing, periorbital wrinkling, and everted lips may also be seen. A seborrheic- or atopic-like dermatitis that evolves into erythroderma may serve as a clue to the diagnosis142, and reticulated hyperpigmentation is occasionally observed. Extracutaneous inflammatory manifestations can include colitis, which affects ~25% of patients, and chronic arthritis. The immunodeficiency results in recurrent pyogenic bacterial infections, especially of the skin and respiratory tract, as well as opportunistic infections. It is characterized by a poor antibody response to polysaccharide antigens, dysgammaglobulinemia (typically elevated IgM and IgA but decreased IgG levels), and defective natural killer cell activity. Patients with the autosomal dominant form of HED-ID also have a severe T-cell deficiency. Occasionally, infants with X-linked HED-ID present with osteopetrosis (abnormally dense bones) and lymphedema141,143. Female carriers, e.g. mothers of affected children, may have mild features of incontinentia pigmenti (see Ch. 62). Treatment Intravenous immunoglobulin (IVIg) administration does not typically decrease the propensity to develop infections. Allogeneic hematopoietic stem cell transplantation can correct the immune defects, but reported recipients have had difficulty achieving engraftment and experienced post-transplant complications such as worsening colitisHidrotic ectodermal dysplasiaHidrotic ectodermal dysplasia was first described in a French-Canadian kindred145 and the ancestry of many affected individuals was traced to a single founder. Subsequently, the disorder has been reported in individuals of varying racial and ethnic backgrounds146. Pathogenesis Hidrotic ectodermal dysplasia is an autosomal dominant condition that is caused by missense mutations in the GJB6 gene, which encodes the connexin 30 protein and is thought to be regulated by the p63 transcription factor147. Connexins oligomerize to form gap junctions that are important for communication between cells (see Ch. 58), and GJB6 is expressed in keratinocytes. Mutations in genes that encode other connexins cause skin disorders ranging from Vohwinkel and keratitis- ichthyosis-deafness (KID) syndromes (GJB2) to erythrokeratodermia variabilis (GJB3 and GJB4) (see Table 58.5). Mutations in GJB6 can also cause non-syndromic, autosomal dominant, digenic (together with a GJB2 mutation) deafness, with normal teeth and hair in affected individuals; less often the inheritance pattern is autosomal recessive. A GJB6 mutation has also been described in a patient with a KID syndrome-like phenotype that included congenital atrichia. Molecular testing of the GJB6 gene is available in clinical laboratories. Clinical Features This condition primarily affects the hair and nails, with normal teeth and sweating. The hair is wiry, brittle and pale; patchy alopecia is common. Both hair loss and nail changes may progress over time. In affected infants, the nails are typically milky white and smaller than normal with gradual thickening throughout childhood. In adults, the nail plates grow slowly, are thick, and separate from the nail bed distally (Fig. 63.18). Hyperkeratosis with stippling of the palms and soles can also be progressive (see Ch. 58). Tiny papules in a grid-like array, corresponding to eccrine acrosyringia, or larger papules coalescing in a cobblestone-like pattern may extend from the palms and soles onto the dorsal surface of the digits, especially distally (see Fig. 63.18 and Fig. 58.10); the latter corresponds to where the dermatoglyphics are more prominent. Similar papules may also occur on the extensor surfaces of the extremities. Oral leukoplakia has been described, and sparse eyelashes may predispose patients to conjunctivitis and blepharitis. Pathology Histologic evaluation of thickened palms and soles shows orthohyperkeratosis with a normal granular layer. Eccrine syringofibroadenomatosis, which is characterized by proliferation of ductal structures within a fibrovascular stroma, may be observed when papular lesions are biopsied. The hair does not have specific microscopic changes. Differential Diagnosis The hair abnormalities in hidrotic ectodermal dysplasia distinguish it from pachyonychia congenita, which may have similar nail findings. A hidrotic ectodermal dysplasia-like phenotype plus deafness has been reported in a few patients with a GJB2 mutation. Treatment The National Foundation for Ectodermal Dysplasias can provide support to affected individuals and families. Ablation of the nail matrix is occasionally necessary for pain relief, and patients with substantial alopecia may choose to use hairpieces. Management of hyperkeratotic palms and soles is difficult; similar strategies to those used for the palmoplantar keratodermas, e.g. α-hydroxy acids, urea, soaking and paring, can be employed.Witkop tooth and nail syndromeFirst described in 1965, this autosomal dominant disorder is probably more common than suggested by the relatively small number of reports in the literature148. Affected individuals have small, thin, brittle nail plates that grow slowly, and koilonychia may be evident at birth. The toenails are usually more prominently involved than the fingernails, and nail abnormalities tend to improve with age. Thin, fine scalp hair is an occasional feature. The primary teeth may be normal or small and/or peg-shaped (Fig. 63.19). There is usually prolonged retention of primary teeth and partially or totally absent secondary dentition, especially the mandibular incisors, second molars and maxillary canines. A mutation in MSX1 (muscle segment homeobox 1), which is expressed in developing teeth and nail beds in mice, has been identified in a family with Witkop tooth and nail syndrome149. Mutations in MSX1 have also been described in families with isolated tooth agenesis or non-syndromic cleft lip and/or palate. MSX1 is a transcription factor that has roles in the development of teeth and presumably nails. Fried tooth and nail syndrome represents a similar condition with autosomal recessive inheritance and more consistent hair abnormalitiesANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE SYNDROMEThis autosomal dominant ectodermal dysplasia, first described in 1976150, has been reported in ethnically and geographically diverse individuals and families151. Pathogenesis The ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is caused by mutations in the region of the TP63 gene that encodes the p63 protein's sterile alpha motif (SAM) domain152. p63, a transcription factor, is expressed within basal keratinocytes of the skin, which have a high proliferative capacity that is lost in differentiated keratinocytes. The p63 protein has multiple isotypes, with the SAM domain present in only some forms. This helps to explain the phenotypic differences between AEC syndrome and ectodermal dysplasia-ectrodactyly-clefting (EEC) syndrome (see Table 63.12 and below), which is due to mutations within the DNA-binding domain of TP63152,153. Clinical Features This disorder is evident at birth. Up to 90% of affected infants present with erythroderma, peeling skin or erosions, which can result in life-threatening infectious complications (Fig. 63.20A). The scalp is almost always involved, and a chronic, erosive scalp dermatitis is common (Fig. 63.20B,C). The scalp hair is wiry and usually lightly pigmented and sparse, often with patchy alopecia. Some degree of nail dystrophy is typically evident, with findings ranging from hyperconvex, thickened nail plates to anonychia. Patients may have decreased sweating and heat intolerance154,155. Patients often develop abnormal granulation tissue and recurrent bacterial infections of the skin. Cribriform and stellate scarring tends to occur in a shawl-like distribution on the shoulders and upper trunk154. Progressive reticulated hyperpigmentation frequently appears in intertriginous areas, and hypopigmentation of the scalp and face may be seen in children with darkly pigmented skin. Congenital strands of tissue between the eyelids (ankyloblepharon adnatum filiforme) are observed in approximately three-quarters of affected individuals (Fig. 63.20D). These may lyse spontaneously, even prior to birth, or require surgical correction. The lacrimal ducts may be atretic. Almost all patients with AEC syndrome are born with a cleft palate with or without a cleft lip. Malformed external ears and recurrent otitis media with secondary conductive hearing loss are common156. Dental abnormalities include hypodontia and misshapen (e.g. conical) teeth, and most patients have maxillary hypoplasia. Gastroesophageal reflux develops in the majority of AEC patients, while one-quarter of affected children fail to thrive and require gastrostomy placement157. Hypospadias affects up to 80% of male patients, and supernumerary nipples and/or ectopic breast tissue have been described158. Limb abnormalities are more common in AEC syndrome than once thought154,155,159; these malformations, which are typically less severe than the defects seen in EEC syndrome (see below), can include syndactyly (partial or complete), camptodactyly, brachydactyly, and even ectrodactylyPathology Hair shaft abnormalities such as pili torti and pili trianguli et canaliculi may be observed. Histopathologic changes are nonspecific and often include mild epidermal atrophy and dermal melanophages160. Differential Diagnosis Rapp-Hodgkin syndrome, once considered to be a distinct entity, is now thought to fall within the AEC spectrum. Affected individuals have heterozygous mutations in the SAM domain of TP63; other than a lack of ankyloblepharon, clinical findings overlap with those of AEC syndrome, including maxillary hypoplasia, cleft palate ± lip, nail dystrophy, and abnormalities of the teeth and hair161. The clinical features of AEC also overlap with those of curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS), which may be caused by homozygous mutations in the receptor-interacting serine-threonine kinase 4 gene (RIPK4) that is a direct transcriptional target of p63162. The peeling erythroderma of neonates with AEC syndrome can lead to a misdiagnosis of epidermolysis bullosa or congenital ichthyosis. Treatment Surgical repair of oral clefting is usually necessary. Treatment for the erosive scalp dermatitis should be gentle and non-occlusive, with surveillance for and treatment of secondary infections. Debridement often causes erosions to worsen, and skin grafts typically fail. Ulceration and granulation tissue may be very difficult to treat, and healing tends to be slow.ECTODERMAL DYSPLASIA-ECTRODACTYLY- CLEFTING SYNDROMEPathogenesis Ectodermal dysplasia-ectrodactyly-clefting (EEC) syndrome is an autosomal dominant disorder caused by mutations in the region of the TP63 gene that encodes the protein's DNA-binding domain163,164. These mutations disrupt the ability of the p63 transcription factor, which is expressed in proliferating epidermal basal cells, to regulate gene expression. TP63 mutations also occur in several related autosomal dominant disorders, including non-syndromic split hand/foot malformation (minority of affected families), limb-mammary syndrome and ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome, as well as in AEC syndrome (see Table 63.12 and above). Patients with EEC syndrome typically have missense mutations within the DNA-binding domain that differ from those seen in the other disorders164. Molecular testing for TP63 mutations is commercially available. Clinical Features The ectodermal changes in this highly variable condition may be quite mild165. The scalp hair is usually light in color and coarse. It may be sparse and grow slowly. The secondary sexual hair may also be affected. Scalp folliculitis and dermatitis are rare166,167. Approximately 80% of affected individuals have transverse ridging, pitting, and slow growth of the nail plates. Xerotic skin and palmoplantar hyperkeratosis can occur, and sweating is usually normal. Clefting of the palate/lip occurs in ~50% of affected individuals, and additional oral abnormalities include enamel hypoplasia, hypodontia, and premature loss of secondary teeth. Lacrimal duct defects leading to blepharitis and dacryocystitis are frequently present, and limbal stem cell deficiency can result in photophobia and keratopathy as well as corneal ulceration and scarring168. Secondary conductive hearing loss is also common, and choanal atresia is an occasional manifestation. Ectrodactyly, a specific split-hand/foot malformation due to failure of normal development of the central digits, represents a defining feature of EEC syndrome (Fig. 63.21). The ectrodactyly is frequently asymmetric, usually with more severe involvement of the feet than the hands. Intrafamilial variability is marked. Genitourinary abnormalities are an under-appreciated manifestation of EEC syndrome and may be associated with dysplasia of the urogenital epithelium; renal and urogenital malformations affect more than one-third of patients and can result in hydronephrosis.ECTODERMAL DYSPLASIA-ECTRODACTYLY- CLEFTING SYNDROMEPathology Histologic features are neither diagnostic nor specific. Differential Diagnosis The presence of split-hand/foot malformations and the absence of ankyloblepharon or cutaneous erosions help to distinguish EEC syndrome from AEC syndrome. The findings that differentiate limb-mammary syndrome and ADULT syndrome from EEC are presented in Table 63.12. Other ectodermal dysplasias that feature digital abnormalities include ectodermal dysplasia-ectrodactyly-macular dystrophy (EEM) syndrome, cleft lip/palate ectodermal dysplasia, oculodentodigital dysplasia, and ulnar-mammary syndrome (see Tables 63.13 and 64.6). Although Goltz syndrome (focal dermal hypoplasia) can present with split-hand/foot and other digital malformations, nail dystrophy, sparse hair, dental anomalies and (occasionally) cleft lip/palate, it is easily recognized based on the highly characteristic skin findings as well as ocular and additional skeletal (e.g. osteopathia striata) defects (see Ch. 62). Lastly, the popliteal pterygium syndrome, which is caused by mutations in the interferon regulatory factor 6 gene (IRF6) that is transcriptionally activated by p63, has overlapping features (see Ch. 64). Treatment As for the other ectodermal dysplasias with oral clefting and lacrimal abnormalities, management involves a multidisciplinary approach. Limb defects may be ameliorated by surgical interventions. All affected individuals should be screened with a renal ultrasound. The small compound APR-246/PRIMA-1MET, which was developed to activate mutant p53 in cancer cells, was found in vitro to rescue impaired epidermal and corneal differentiation in cells from EEC patients, providing a potential approach to therapy1