Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward (Yung and Newton-Bishop, 2005). Rombo syndrome (180730) has similar features, but shows autosomal dominant inheritance.

Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.

Floating-Harbor syndrome (FHS) is characterized by typical craniofacial features; low birth weight, normal head circumference, and short stature; bone age delay that normalizes between ages six and 12 years; skeletal anomalies (brachydactyly, clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities); severe receptive and expressive language impairment; hypernasality and high-pitched voice; and intellectual disability that is typically mild to moderate. Difficulties with temperament and behavior that are present in many children tend to improve in adulthood. Other features can include hyperopia and/or strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis / renal pelviectasis, cysts, and/or agenesis), and genital anomalies (e.g., hypospadias and/or undescended testes).

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

A rare genetic syndromic intellectual disability disorder with characteristics of mild to profound intellectual disability, delayed speech, obesity, ocular anomalies (blepharophimosis, blepharoptosis, hyperopic astigmatism, decreased visual acuity, strabismus, abducens nerve palsy, and/or accommodative esotropia), and dermal manifestations, such as chronic atopic dermatitis. Associated craniofacial dysmorphism includes macrocephaly, maxillary hypoplasia, mandibular prognathism and crowding of teeth.

Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome with characteristics of hair, skin and teeth anomalies, facial dysmorphism with cleft lip and palate, cutaneous syndactyly and, in some cases, intellectual disability.The prevalence is unknown but to date, less than 50 cases have been described in the literature. Caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Transmission is autosomal recessive.

Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

EVEN-plus syndrome (EVPLS) is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015).

IMD11B is an autosomal dominant disorder of immune dysfunction characterized by onset of moderate to severe atopic dermatitis in early childhood. Some patients may have recurrent infections and other variable immune abnormalities. Laboratory studies show defects in T-cell activation, increased IgE, and eosinophilia (summary by Ma et al., 2017).

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006).

Peeling skin syndrome-6 (PSS6) is characterized by generalized ichthyotic dry skin and bullous peeling lesions on the trunk and limbs at sites of minor trauma. There is residual hyperpigmentation in areas of healing, but no scarring. Skin symptoms are exacerbated by warmth and humidity; however, the disorder improves markedly with age (Bolling et al., 2018; Mohamad et al., 2018). For a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (270300).

Hyper-IgE syndrome-3 with recurrent infections (HIES3) is an autosomal recessive immunologic disorder characterized by childhood onset of atopic dermatitis, skin infections particularly with Staphylococcus aureus, recurrent sinopulmonary infections, and increased serum IgE and IgG. Patients are susceptible to bacterial and fungal infections, including chronic mucocutaneous candidiasis. Immunologic workup shows impaired differentiation of CD4+ T cells into T-helper 17 cells, decreased memory B cells, and often decreased NK cells (summary by Beziat et al., 2018). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Infantile T-cell lymphopenia with or without nail dystrophy (TLIND) is an autosomal dominant disorder characterized by decreased numbers of T cells, particularly cytotoxic CD8+ T cells, usually apparent from infancy. Patients are often identified through newborn screening with the finding of low levels of T-cell receptor excision circles (TRECs). Affected individuals tend to be more susceptible to recurrent infections, mainly respiratory viral infections. However, the severity is highly variable, and patients usually improve with age later in childhood and as adults, even if CD8+ T cells remain decreased compared to normal. Additional features may include a small thymic shadow, indicative of impaired thymic development, skin abnormalities, such as atopic dermatitis, and nail dystrophy. As rare patients may develop more serious infections, affected individuals should be monitored. Bone marrow transplantation is not curative (summary by Bosticardo et al., 2019).

Hyper-IgE syndrome-5 with recurrent infections (HEIS5) is an autosomal recessive immunologic disorder characterized by onset of recurrent sinopulmonary and deep skin infections in early childhood. The infections are mostly caused by bacteria, including H. influenza and Staphylococcus aureus. Additional features include atopic dermatitis, impaired inflammatory responses during infection, increased serum IgE, and increased IL6 (147620) (summary by Spencer et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Autoinflammation, immune dysregulation, and eosinophilia (AIIDE) is an autosomal dominant disorder characterized by onset of severe atopic dermatitis and chronic gastrointestinal inflammation, mainly involving the colon, in infancy or early childhood. Affected individuals tend to have asthma and food or environmental allergies, as well as poor overall growth with short stature. Severe liver involvement has also been reported (Takeichi et al., 2021). Laboratory studies show increased eosinophils with normal or increased IgE levels, as well as evidence of a hyperactive immune state, including increased erythrocyte sedimentation rate and C-reactive protein. Treatment with JAK inhibitors, such as ruxolitinib and tofacitinib, results in dramatic clinical improvement (summary by Gruber et al., 2020).

Cleft palate, proliferative retinopathy, and developmental delay (CPPRDD) is characterized by motor and speech delay, with intellectual disability ranging from mild to severe. Brain imaging shows ventriculomegaly as well as other malformations (Harel et al., 2019).

VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).

Intellectual disability and myopathy syndrome (IDMYS) is an autosomal recessive developmental disorder characterized by global developmental delay with mildly impaired intellectual development, hypotonia, muscle weakness and fatigue, and white matter abnormalities on brain imaging. Variable additional features may include sensorineural hearing loss, dysmorphic facies, and progressive heart disease (summary by Smeland et al., 2019).

Hyper-IgE syndrome-4A with recurrent infections (HIES4A) is an autosomal dominant immunologic disorder characterized by recurrent, mainly sinopulmonary infections associated with increased serum IgE. The phenotype is variable, even within families. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The IL6ST mutations are loss-of-function, although the truncated mutant proteins are expressed and interfere with the wildtype protein in a dominant-negative manner by disrupting IL6 (147620) and IL11 (147681) signaling (summary by Beziat et al., 2020). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder characterized by childhood onset of failure to thrive, skin manifestations, pancytopenia, and susceptibility to recurrent infections (Harapas et al., 2022).

Systemic autoinflammatory disease with vasculitis (SAIDV) is an autosomal dominant disorder that manifests soon after birth with features such as purpuric skin rash, fever, hepatosplenomegaly, and elevated C-reactive protein (CRP; 123260). Laboratory studies may show leukocytosis, thrombocytopenia, and autoantibodies. A subset of patients develop progressive liver involvement that may result in fibrosis. Other systemic features, such as periorbital edema, conjunctivitis, infections, abdominal pain, and arthralgia are usually observed. Mutations occur de novo. De Jesus et al. (2023) referred to this disorder as LAVLI (LYN kinase-associated vasculopathy and liver fibrosis).

Hyper-IgE syndrome-6 with recurrent infections (HIES6) is an autosomal dominant immunologic disorder characterized by early-childhood onset of severe refractory atopic dermatitis, IgE-mediated food and drug allergies, asthma, and eosinophilic esophagitis. Laboratory studies show increased serum IgE levels and eosinophilia. Affected individuals are susceptible to life-threatening anaphylaxis. Additional features may include allergic rhinitis, recurrent secondary infections (bacterial, viral, fungal), and short stature. Rare patients show intracerebral vascular abnormalities, including the Circle of Willis, increased risk of ruptured aneurysm, and B-cell lymphoma. The disorder results from immune dysregulation with inappropriate activation of inflammatory signaling pathways associated with a Th2 phenotype. Treatment with an IL4 (147780)/IL13 (147683) inhibitor (dupilumab) or JAK inhibitor results in clinical improvement. Sharma et al. (2023) classified this disease as a 'primary atopic disorder' (PAD). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Childhood-onset variegate porphyria (VPCO), also called 'homozygous' variegate porphyria, is a rare disorder of heme biosynthesis characterized by severe PPOX deficiency, onset of photosensitization by porphyrins in early childhood, skeletal abnormalities of the hand, and, less consistently, short stature, impaired intellectual development, and seizures. The term 'homozygous' refers to the presence of mutations on both alleles of the PPOX gene, resulting in earlier onset and more severe manifestations than those seen in variegate porphyria (VP), a low-penetrance disorder inherited as an autosomal dominant trait (summary by Roberts et al., 1998). Heterozygous family members of VPCO patients are usually clinically silent, but symptomatic heterozygotes have been reported (Mustajoki et al., 1987; Palmer et al., 2001; Kauppinen et al., 2001). Nomenclature 'Homozygous' variegate porphyria was so designated before the molecular defect in PPOX was elucidated, on the basis of severe reduction in PPOX activity (between 5 and 20% of control values) compared to that seen in variegate porphyria (approximately 50% reduction), in which autosomal dominant transmission had been observed. It is probable that most cases of 'homozygous' variegate porphyria actually result from compound heterozygosity for PPOX mutations (Frank et al., 1998; Palmer et al., 2001).

Folate-responsive immunodeficiency-114 (IMD114) is an autosomal recessive immunologic disorder characterized by the onset of oral ulcers and recurrent skin and respiratory infections in early infancy. Affected individuals have lip fissures, skin sores and abscesses, genital dermatitis, chronic diarrhea, and poor overall growth. Laboratory studies show megaloblastic anemia, thrombocytopenia, and lymphopenia with decreased Ig levels. Some individuals have global developmental delay, often with brain imaging abnormalities. Treatment with folic acid supplementation results in significant clinical improvement of the hematologic and immunologic abnormalities, although neurologic abnormalities, if already present, do not respond to treatment. Early intervention and treatment with folic acid supplementation may prevent or delay neurologic deficits in affected infants (Gok et al., 2023; Shiraishi et al., 2023).