MedGen

Birk-Aharoni syndrome (BKAH) is a severe neurodevelopmental disorder characterized developmental delay, impaired intellectual development, absent speech, spastic tetraplegia with central hypotonia, chorea, inability to walk, hearing loss, micropenis, undescended testes, and mildly elevated liver enzymes (Aharoni et al., 2022). [from OMIM]

Neurodevelopmental disorder with microcephaly, hypotonia, and absent language (NEDMHAL) is a severe autosomal recessive disorder characterized by the constellation of these features. Behavioral problems and hearing loss are also present (Ansar et al., 2020). [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]

Deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP) is characterized by early-onset of deafness, cataract, severe developmental delay, and severely impaired intellectual development. Patients later develop polyneuropathy of the lower extremities, associated with depigmentation of the hair in that area (Kroll-Hermi et al., 2020). [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]

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]

Proteasome-associated autoinflammatory syndrome-3 is an autosomal recessive syndrome with onset in early infancy. Affected individuals present with nodular dermatitis, recurrent fever, myositis, panniculitis-induced lipodystrophy, lymphadenopathy, and dysregulation of the immune response, particularly associated with abnormal type I interferon-induced gene expression patterns. Additional features are highly variable, but may include joint contractures, hepatosplenomegaly, anemia, thrombocytopenia, recurrent infections, autoantibodies, and hypergammaglobulinemia. Some patients may have intracranial calcifications (summary by Brehm et al., 2015). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040). [from OMIM]

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]

Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21. [from OMIM]

Stankiewicz-Isidor syndrome (STISS) is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems (summary by Kury et al., 2017). [from OMIM]

Autosomal recessive deafness-123 (DFNB123) is characterized by nonsyndromic bilateral severe to profound hearing impairment, with onset as early as the first decade of life (Schrauwen et al., 2023). [from OMIM]

Autosomal dominant severe congenital neutropenia-11 (SCN11) is characterized by the onset of recurrent infections, mainly bacterial, in early childhood. Laboratory studies show severe neutropenia due to maturation arrest and impaired development of myeloid cells. Other leukocyte subsets, including B cells and NK cells, may also be subtly affected. Patients should be followed for possible renal dysfunction (Van Nieuwenhove et al., 2020). For discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700). [from OMIM]

Common variable immunodeficiency-15 (CVID15) is an autosomal dominant immunologic disorder characterized by the onset of severe recurrent infections in infancy or early childhood. Laboratory studies show hypogammaglobulinemia with antibody deficiencies of IgM, IgG, and IgA due to impaired plasma cell homeostasis, although other B cell subset numbers are normal. T and NK cells are also normal. Treatment with IV Ig results in a favorable clinical response to recurrent infections (Schubert et al., 2018). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594). [from OMIM]

Autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5) is characterized by the onset of progressive chronic renal disease in the first decades of life. Mild hyperuricemia may be present, but gout, hypertension, and proteinuria are usually absent. The disease may be associated with anemia or neutropenia. Some patients may have additional findings, including poor overall growth and impaired cognitive function. Renal biopsy shows tubulointerstitial abnormalities with atrophic tubules and fibrosis; secondary glomerular abnormalities and simple cysts may also be present (summary by Bolar et al., 2016). For a discussion of genetic heterogeneity and revised nomenclature of ADTKD, see ADTKD1 (162000). [from OMIM]

Any bacteremia, susceptibility in which the cause of the disease is a mutation in the TIRAP gene. [from MONDO]

Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998). Genetic Heterogeneity of Thrombocythemia THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34, and THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013). [from OMIM]

Carbamazepine is an aromatic anticonvulsant used to treat epilepsy and other seizure disorders, as well as bipolar disorder and trigeminal neuralgia. Carbamazepine can cause a variety of cutaneous adverse reactions, ranging from mild maculopapular eruptions to Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The genetic variant HLA-B*15:02 is associated with the risk of SJS/TEN. Patients who have at least one copy of the HLA-B*15:02 allele (considered HLA-B*15:02-positive) have a significantly increased risk for SJS/TEN compared to non-carriers, and it is recommended that they receive an alternate drug. It is important to note that it is possible for a patient without HLA-B*15:02 to develop SJS/TEN. Guidelines regarding the use of pharmacogenomic tests in dosing for carbamazepine have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Allopurinol is widely prescribed for the treatment of hyperuricemia and gout. An estimated 25-30% of gout patients in the UK and the US are treated with allopurinol. However, 0.1-0.4% of patients treated with allopurinol experience severe cutaneous adverse reactions (SCAR), including drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The genetic variant HLA-B*58:01, along with non-genetic factors, is known to be associated with this risk. Patients who are HLA-B*58:01-positive (having at least one copy of the HLA-B*58:01 allele) have a significantly increased risk of allopurinol-induced SCAR compared to those who are negative for this allele. It is still possible for a HLA-B*58:01 negative patient to develop SCAR on allopurinol. Guidelines regarding the use of pharmacogenomic tests in dosing for allopurinol have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]