The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.

Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant genodermatosis characterized by onset in infancy of a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Patients develop cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses (Witkop et al., 1982). Although 1 family was reported to have progressive severe interstitial lung disease (Witkop et al., 1979), this feature has not been reported in other families and is not considered a criterion for diagnosis. However, the clinical triad of nonscarring alopecia, well-demarcated fiery red mucosa, and psoriasiform perineal involvement has been consistently observed (review by Boralevi et al., 2005).

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

APC-associated polyposis conditions include (classic or attenuated) familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). FAP is a colorectal cancer (CRC) predisposition syndrome that can manifest in either classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36 years). For those with the classic form of FAP, 95% of individuals have polyps by age 35 years; CRC is inevitable without colectomy. The mean age of CRC diagnosis in untreated individuals is 39 years (range 34-43 years). The attenuated form is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of CRC at a later age than in classic FAP. For those with an attenuated form, there is a 70% lifetime risk of CRC and the mean age of diagnosis is 50-55 years. Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoid tumors, adrenal masses, and other associated cancers. GAPPS is characterized by proximal gastric polyposis, increased risk of gastric adenocarcinoma, and no duodenal or colonic involvement in most individuals reported.