Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.

A multifocal, multisystem form of Langerhans-cell histiocytosis. There is involvement of multiple organ systems including the bones, skin, liver, spleen, and lymph nodes. Patients are usually infants presenting with fever, hepatosplenomegaly, lymphadenopathy, bone and skin lesions, and pancytopenia.

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.

If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

A rare disorder of mineral absorption and transport characterized by hypocupremia that manifests as failure to thrive, mild anemia, repeated seizures, hypotonia and seborrheic skin. Spurring of the femur and tibia are also noted on radiographic imaging. Symptoms are reversible or improve with supplements of oral copper. There have been no further descriptions in the literature since 1982.

A rare genetic epidermal disorder with characteristics of a chronic diffuse fine scaly erythematous rash on the face (predominantly the chin, nasolabial folds, eyebrows) around the earlobes and over the scalp, associated with hyperkeratosis over elbows, knees, palms, soles and metacarpophalangeal joints, in the absence of associated rheumatological or neurological disorders. Cold weather, emotional stress and strenuous physical activity may exacerbate symptoms. There is evidence the disease is caused by mutation in the ZNF750 gene.

3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by Baumgartner et al., 2001). Also see 3-methylcrotonylglycinuria I (MCC1D; 210200), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010).

Autosomal dominant primary hypertrophic osteoarthropathy (PHOAD) is characterized by 3 major features: digital clubbing, periostosis, and pachydermia. Patients may also experience joint swelling and pain, and some have reported gastrointestinal symptoms, including watery diarrhea. Males are more commonly affected, and more severely affected, than females (Lee et al., 2016; Xu et al., 2021). Touraine et al. (1935) recognized pachydermoperiostosis (PDP) as a familial disorder with 3 presentations or forms: a complete form with periostosis and pachydermia, an incomplete form without pachydermia, and a forme fruste with pachydermia and minimal skeletal changes. Genetic Heterogeneity Autosomal recessive forms of PHO have been reported (see 259100), including PHOAR2E (614441), which is also caused by mutation in the SLCO2A1 gene. Patients with autosomal recessive PHO do not experience gastrointestinal symptoms.

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

PHOAR2-enteropathy syndrome (PHOAR2E) is characterized by primary hypertrophic osteoarthropathy (PHO) and/or chronic nonspecific ulcers (CNSU) of the small intestine. The cardinal features of PHO are digital clubbing, pachydermia, and periostosis; other manifestations include swelling and pain of the large joints, hyperhidrosis, seborrhea, and acne. CNSU often presents with chronic unexplained anemia and abdominal pain, and patients may exhibit edema due to hypoalbuminemia. Radiologic imaging or endoscopy shows multiple small ulcers, predominantly in the ileum, although the stomach, duodenum, and jejunum are often involved. PHO is more frequent and more severe in male patients, who often also report watery diarrhea, whereas CNSU is more often diagnosed in female patients, who may also show features of PHO such as digital clubbing or arthralgias and swelling of the joints. The same mutations in the SLCO2A1 gene have been reported in patients presenting with either diagnosis, and presumed sex-related modifiers of the manifestations of disease or other genotype/phenotype correlates have yet to be elucidated (Li et al., 2017; Umeno et al., 2018; Hong et al., 2022; Kimball et al., 2024). For a discussion of genetic heterogeneity of PHO, see PHOAR1 (259100).

Chronic mucocutaneous candidiasis is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae with Candida albicans, and sometimes by staphylococcal skin infections (summary by Boisson et al., 2013). For a discussion of genetic heterogeneity of familial candidiasis, see CANDF1 (114580).

Autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1) is a rare familial disorder characterized by digital clubbing, osteoarthropathy, and acroosteolysis, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease (summary by Uppal et al., 2008; Radhakrishnan et al., 2020). Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (Uppal et al., 2008). Touraine et al. (1935) recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. Genetic Heterogeneity Autosomal recessive primary hypertrophic osteoarthropathy-2-enteropathy syndrome (PHOAR2E; 614441) is caused by mutation in the SLCO2A1 gene (601460) on chromosome 3q22. Families with an autosomal dominant form of primary hypertrophic osteoarthropathy, in which patients may also experience gastrointestinal symptoms, have been reported (PHOAD; 167100).

Immunodeficiency-58 is an autosomal recessive primary immunologic disorder characterized by early-onset skin lesions, including eczematous dermatitis, infectious abscesses, and warts, recurrent respiratory infections or allergies, and chronic persistent infections with candida, Molluscum contagiosum, mycobacteria, EBV, bacteria, and viruses. Some patients may have gastrointestinal involvement, including inflammatory bowel disease, EBV+ smooth muscle tumors, and esophagitis. Immunologic analysis shows defective T-cell function with decreased Treg cells and deficient CD3/CD28 costimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired (summary by Wang et al., 2016 and Alazami et al., 2018).

A rare genetic metabolic liver disease with characteristics of progressive neurodegeneration, cutaneous abnormalities including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations including microdontia, widely spaced and pointed teeth with delayed eruption and gingival overgrowth.

Agammaglobulinemia-9 (AGM9) is an autosomal recessive primary immunodeficiency characterized by recurrent bacterial infections associated with agammaglobulinemia and absence of circulating B cells. Additional features include failure to thrive and skin involvement. The severity is variable: more severe cases may require hematopoietic stem cell transplantation, whereas others can be treated effectively with Ig replacement therapy (summary by Anzilotti et al., 2019). For a discussion of genetic heterogeneity of autosomal agammaglobulinemia, see AGM1 (601495).