A rare disorder characterised by hemolytic anemia, associated with metabolic acidosis and 5-oxoprolinuria in moderate forms, and with progressive neurological symptoms and recurrent bacterial infections in the most severe forms. [from ORDO]

A group of muscle diseases with basis in CAV3, which encodes caveolin-3, a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo. It is the only gene in which pathogenic variants are known to cause caveolinopathies. Sequence analysis identifies pathogenic variants in more than 99% of affected individuals [from MONDO]

Stickler syndrome type VI (STL6) is characterized by early-onset progressive hearing loss and progressive myopia, with variable manifestation of facial dysmorphism and skeletal anomalies (Nixon et al., 2019; Rad et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of Stickler syndrome, see STL1 (108300). [from OMIM]

Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013). Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain. Genetic Heterogeneity of Mitochondrial Complex II Deficiency See MC2DN2 (619166), caused by mutation in the SDHAF1 gene (612848) on chromosome 19q13; MC2DN3 (619167), caused by mutation in the SDHD gene (602690) on chromosome 11q23; and MC2DN4 (619224), caused by mutation in the SDHB gene (185470) on chromosome 1p36. Fullerton et al. (2020) reviewed the genetic basis of isolated mitochondrial complex II deficiency. [from OMIM]

A rare genetic parenchymatous liver disease with characteristics of infantile or early childhood onset of recurrent episodes of acute liver failure precipitated by a febrile illness. During the life-threatening episodes, patients present with vomiting, lethargy, jaundice as well as elevated levels of liver enzymes and coagulopathy. There is usually complete recovery between the episodes with conservative treatment. [from SNOMEDCT_US]

Autosomal dominant isolated macrothrombocytopenia-1 (MACTHC1) is characterized by the finding of low platelet numbers and abnormally large platelets with irregular shapes. Affected individuals do not have increased bleeding episodes and platelet function is normal; macrothrombocytopenia is usually an incidental laboratory finding (Kunishima et al., 2009). Genetic Heterogeneity of Isolated Macrothrombocytopenia See also MACTHC2 (619840), caused by mutation in the TUBA8 gene (605742) on chromosome 22q11. [from OMIM]

Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy. [from GeneReviews]

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal. [from GeneReviews]

ZAP70-related combined immunodeficiency (ZAP70-related CID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower-respiratory infections and oral candidiasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT). [from GeneReviews]

Myopia-28 (MYP28) is characterized by early-onset high myopia in the first decade of life. Retinal detachment may occur, and early-onset cataract has been reported (Li et al., 2016; Maddirevula et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of myopia, see MYP2 (160700). [from OMIM]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean onset of symptoms (usually a syncopal episode) is between age seven and 12 years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Sudden death may be the first manifestation of the disease. [from GeneReviews]

Cytosolic phosphoenolpyruvate carboxykinase deficiency causes a defect in gluconeogenesis that results in a 'biochemical signature' of fasting hypoglycemia with high tricarboxylic acid cycle intermediate excretion, particularly of fumarate. Other biochemical anomalies that may be seen during metabolic crisis include ketonuria, dicarboxylic aciduria, and urea cycle dysfunction (Vieira et al., 2017). See PCKDM (261650) for a discussion of mitochondrial PCK (PEPCK2; 614095) deficiency. [from OMIM]

Congenital dyserythropoietic anemia type IIIa (CDAN3A) is a rare autosomal dominant hematologic disorder characterized by nonprogressive mild to moderate hemolytic anemia, macrocytosis in the peripheral blood, intravascular hemolysis, and giant multinucleated erythroblasts in the bone marrow. The disorder results from ineffective erythropoiesis. Laboratory studies show evidence of intravascular hemolysis, including increased thymidine kinase, lactate dehydrogenase, and/or undetectable haptoglobin (summary by Lind et al., 1995; Liljeholm et al., 2013). For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see 224120. [from OMIM]

Immunodeficiency-104 (IMD104) is an autosomal recessive disorder characterized by the onset of recurrent infections in early infancy. Manifestations may include oral thrush, fever, and failure to thrive. Some patients have lymphadenopathy and hepatosplenomegaly, whereas others have absence of lymph nodes and lack a thymic shadow. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, variable hypogammaglobulinemia, and normal NK cells. The disorder is caused by a defect in IL7 (146660) signaling due to a mutant IL7 receptor. Hematopoietic stem cell transplantation may be curative (Roifman et al., 2000 and Giliani et al., 2005). Giliani et al. (2005) provided a detailed review of IL7R deficiency, including discussion of the IL7R gene and its function in the immune system, clinical features of the disorder, and experiences with hematopoietic stem cell transplant as treatment. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457. [from OMIM]

Autosomal recessive SPG9B is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (summary by Coutelier et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800). [from OMIM]

Autosomal dominant spastic paraplegia-9A is a neurologic disorder characterized by onset of slowly progressive spasticity mainly affecting the lower limbs. The age at onset usually ranges from adolescence to adulthood, and patients have gait difficulties, motor neuropathy, and dysarthria. Additional variable features include cerebellar signs, cataract, pes cavus, and urinary urgency (summary by Coutelier et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). [from OMIM]

Lymphoproliferative syndrome-3 (LPFS3) is an autosomal recessive early-onset immunologic disorder characterized by increased susceptibility to Epstein-Barr virus (EBV) infection in B cells, resulting in abnormal B-cell proliferation and increased susceptibility to B-cell malignancies, including Hodgkin lymphoma. Patients usually have hypogammaglobulinemia without lymphopenia, although some subsets of immune cells may be low and some patients may have recurrent infections. The disorder results from impaired signaling from proliferating B cells to effector T cells that provide immune surveillance. There may be an increased risk of solid tumors in heterozygous carriers (summary by Abolhassani et al., 2017). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240). [from OMIM]

IMD50 is an X-linked recessive primary immunodeficiency characterized by the onset of recurrent bacterial or varicella zoster virus (VZV) infections in early childhood. Laboratory studies show profound lymphopenia, hypogammaglobulinemia, poor immune response to vaccine antigens, and fluctuating neutropenia. The disorder does not affect overall patient survival (summary by Lagresle-Peyrou et al., 2016). [from OMIM]

Recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP) is an autosomal recessive disorder characterized by onset of severe gastrointestinal mucosal ulceration in early childhood. Affected individuals may have secondary iron deficiency anemia or malnourishment. Studies of platelet aggregation show a functional defect associated with decreased thromboxane-A2 production and decreased eicosanoid biosynthesis. The gastrointestinal disease is believed to result from decreased or absent production of prostaglandins that protect the gut mucosa (summary by Adler et al., 2008 and Faioni et al., 2014). [from OMIM]

Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (summary by Ercan-Sencicek et al., 2015). [from OMIM]