MedGen

Autosomal dominant intellectual developmental disorder-73 (MRD73) is a highly variable neurodevelopmental disorder characterized by impaired intellectual development that ranges from mild to severe, speech delay, behavioral abnormalities, and nonspecific dysmorphic facial features (Janssen et al., 2022). [from OMIM]

X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature (de Jesus et al., 2020 and Lee et al., 2022). [from OMIM]

Immunodeficiency-106 (IMD106) is an autosomal recessive immunologic disorder characterized by increased susceptibility to viral infections beginning in infancy or early childhood. Some patients present with recurrent respiratory infections or other viral infections. In many cases, the susceptibility to viral infections due to IMD106 only becomes apparent after initial vaccination with live attenuated viral (LAV) vaccines, most notably MMR and yellow fever. A subset of IMD106 patients who demonstrate adverse reactions to MMR or other LAV vaccinations develop a severe acute hyperinflammatory response reminiscent of hemophagocytic lymphohistiocytosis (HLH) and may show encephalopathy, acute respiratory distress syndrome, and multiorgan failure. However, some patients with IMD106 tolerate MMR vaccination without sequelae. IFNAR1 deficiency may also predispose to severe respiratory infection with SARS-CoV-2 and to herpes simplex virus-1 (HSV1) encephalitis (HSE). The disorder results from an impaired type I interferon signaling response (Bastard et al., 2022). [from OMIM]

Immunodeficiency-95 (IMD95) is an autosomal recessive disorder characterized predominantly by the onset of recurrent and severe viral respiratory infections in infancy or early childhood. Affected individuals often require hospitalization or respiratory support for these infections, which include human rhinovirus (HRV) and RSV. Immunologic workup is usually normal, although some mild abnormalities may be observed. The disorder results from a loss of ability of the innate immune system to sense viral genetic information, which causes a lack of interferon (IFN) production, poor response to viral and immunologic stimulation, and failure to control viral replication (summary by Lamborn et al., 2017, Asgari et al., 2017, Cananzi et al., 2021). [from OMIM]

Dystonia-33 (DYT33) is a neurologic disorder characterized by onset of focal or generalized dystonia in the first decades of life (from early childhood to adolescence). The disorder is slowly progressive and may result in ambulation difficulties, dysarthria, or dysphagia. There is variable expressivity even with a family, as well as incomplete penetrance of the phenotype. Most mutations are in the heterozygous state, but a homozygous mutation with autosomal recessive inheritance has been reported, indicating variable patterns of transmission of DYT33. Some patients may have a more complex neurologic disorder with motor delay, lower limb spasticity, mild developmental delay with cognitive impairments, and nonspecific brain imaging abnormalities. There may be an exacerbation of the symptoms coinciding with viral infection or stress. Deep brain stimulation (DBS) may be therapeutic (summary by Kuipers et al., 2021). [from OMIM]

Bartsocas-Papas syndrome-2 (BPS2) is a severe form of popliteal pterygium disorder characterized by cutaneous webbing across one or more joints, cleft lip and/or palate, syndactyly, and genital malformations (summary by Leslie et al., 2015). [from OMIM]

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). [from OMIM]

Immunodeficiency-69 (IMD69) is an autosomal recessive disorder characterized by increased susceptibility to disseminated mycobacterial infection, including after BCG (bacille Calmette-Guerin) vaccination. Affected individuals develop fever, hepatosplenomegaly, leukocytosis, and thrombocytosis during the acute infection. There appears to be normal immunologic function against other pathogens, including viruses and bacteria. Immunologic work-up shows normal parameters, but patient T and NK cells fail to produce gamma-interferon (IFNG) when stimulated in vitro (summary by Kerner et al., 2020). IMD69 is a form of mendelian susceptibility to mycobacterial disease (MSMD) (see, e.g., IMD27A; 209950). [from OMIM]

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (LEMSPAD) is characterized by a motor-predominant phenotype including motor developmental delay, speech articulation disorder, progressive spastic hemiplegia with hyperreflexia, and age-appropriate cognition (Mao et al., 2020). [from OMIM]

Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) is characterized by global developmental delay apparent in early childhood, followed by episodic neurologic regression or decompensation associated with systemic stress, such as febrile infection. Affected individuals have hypotonia, gait difficulties or ataxia, poor or absent speech with dysarthria, and variable motor abnormalities, including spasticity, dystonia, extrapyramidal signs, and tremor. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities, poor myelination, thin corpus callosum, and generalized cerebral atrophy with enlarged ventricles. The clinical features of the disorder and the abnormal brain imaging findings are progressive (summary by Mao et al., 2020). [from OMIM]

Pseudo-TORCH syndrome-3 (PTORCH3) is an autosomal recessive disorder of immune dysregulation and neuroinflammation apparent from early infancy. Affected individuals have developmental delay with acute episodes of fever and multisystemic organ involvement, including coagulopathy, elevated liver enzymes, and proteinuria, often associated with thrombotic microangiopathy. Brain imaging shows progressive intracranial calcifications, white matter abnormalities, and sometimes cerebral or cerebellar atrophy. Laboratory studies show abnormal elevation of interferon (IFN)-stimulated gene (ISG) transcripts consistent with a type I interferonopathy. The phenotype resembles the sequelae of intrauterine infection, but there is usually no evidence of an infectious agent. The disorder results from defects in negative regulation of the interferon immunologic pathway. Death in early childhood is common (summary by Duncan et al., 2019 and Gruber et al., 2020). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290). [from OMIM]

Immunodeficiency-65 (IMD65) is an autosomal recessive immunologic disorder characterized by onset of recurrent and severe viral infections from early infancy. Affected individuals have impaired ability to fight viral infections, resulting in clinically significant disease, including pneumonia, bronchiectasis, and septic shock. Laboratory studies may show lymphopenia or hypogammaglobulinemia, particularly during infection; more detailed studies show an impaired cellular type I interferon response. Treatment with intravenous immunoglobulin (IVIg) is beneficial. Important features of this disorder include the rapid development of septic shock, as well as poor outcomes after vaccination with live attenuated vaccines; such vaccines should never be administered to patients with known impaired interferon responses (summary by Hernandez et al., 2018 and Bravo Garcia-Morato et al., 2019). [from OMIM]

Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) is characterized by early-onset hypotonia, delayed walking, poor speech, and impaired intellectual development. Additional features may include feeding difficulties, dysmorphic features, and visual defects. Brain imaging tends to show delayed myelination, thin corpus callosum, and/or enlarged ventricles. The severity of the disorder is highly variable; initial evidence suggests that the severity may depend on the type of mutation (summary by Haijes et al., 2019). [from OMIM]

Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a neurologic disorder characterized in most cases by early-onset seizures and variably impaired intellectual development (ID). The severity of neurologic impairment is highly variable: some patients may have refractory seizures and be bedridden with no meaningful speech, whereas others may have treatment-responsive seizures and achieve normal psychomotor development (summary by Li et al., 2019). [from OMIM]

Menke-Hennekam syndrome-2 (MKHK2) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, and hearing impairment are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-2 (RSTS2; 613684), patients with MKHK1 do not resemble the striking phenotype of RSTS2. For a discussion of genetic heterogeneity of Menke-Hennekam syndrome, see MKHK1 (618332). [from OMIM]

Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-1 (RSTS1; 180849), patients with MKHK1 do not resemble the striking phenotype of RSTS1. Genetic Heterogeneity of Menke-Hennekam Syndrome Menke-Hennekam syndrome-2 (MKHK2; 618333) is caused by heterozygous mutation in exons 30 or 31 of the EP300 gene (602700). Mutation elsewhere in that gene results in RSTS2 (613684). [from OMIM]

Immunodeficiency-15B (IMD15B) is an autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T cells. However, functional studies show impaired differentiation and activation of immune cells (summary by Pannicke et al., 2013). [from OMIM]

A small percentage of prostate cancers are hereditary and occur in families. These hereditary cancers are associated with inherited gene variants. Hereditary prostate cancers tend to develop earlier in life than non-inherited (sporadic) cases.

Some cancerous tumors can invade surrounding tissue and spread to other parts of the body. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers. The signs and symptoms of metastatic cancer depend on where the disease has spread. If prostate cancer spreads, cancerous cells most often appear in the lymph nodes, bones, lungs, liver, or brain.

The severity and outcome of prostate cancer varies widely. Early-stage prostate cancer can usually be treated successfully, and some older men have prostate tumors that grow so slowly that they may never cause health problems during their lifetime, even without treatment. In other men, however, the cancer is much more aggressive; in these cases, prostate cancer can be life-threatening.

Early prostate cancer usually does not cause pain, and most affected men exhibit no noticeable symptoms. Men are often diagnosed as the result of health screenings, such as a blood test for a substance called prostate specific antigen (PSA) or a medical exam called a digital rectal exam (DRE). As the tumor grows larger, signs and symptoms can include difficulty starting or stopping the flow of urine, a feeling of not being able to empty the bladder completely, blood in the urine or semen, or pain with ejaculation. However, these changes can also occur with many other genitourinary conditions. Having one or more of these symptoms does not necessarily mean that a man has prostate cancer.

Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate become abnormal, multiply without control or order, and form a tumor. The prostate is a gland that surrounds the male urethra and helps produce semen, the fluid that carries sperm. [from MedlinePlus Genetics]

Immunodeficiency 15A (IMD15A) is an autosomal dominant primary immunodeficiency disorder characterized by relatively late onset of recurrent respiratory tract infections and lymphopenia, combined with immune activation of both CD4+ and CD8+ T cells. One patient presented with inflammatory disease and possible ectodermal defect. [from OMIM]