VEXAS syndrome is an autoinflammatory syndrome caused by a somatic UBA1 (i.e., mosaic or postzygotic) pathogenic variant in hematopoietic stem cells. Because UBA1 is an X-linked gene, VEXAS syndrome mostly affects males; however, females account for about 4% of affected individuals. VEXAS syndrome, characterized by inflammatory and hematologic findings, typically affects males older than age 50 years. The most common inflammatory findings include recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis. Hematologic involvement includes macrocytic anemia, myelodysplastic syndrome (MDS), thrombocytopenia, monoclonal gammopathy of unknown significance, and vacuoles in myeloid and erythroid precursor cells.The diagnosis of VEXAS syndrome is established in an individual with suggestive findings and a UBA1 somatic (also known as mosaic or postzygotic) pathogenic variant identified by molecular genetic testing in peripheral blood and/or bone marrow aspirate, but not skin fibroblasts. Pathogenic variants, although somatic, are typically present at a high variant allele fraction and can be detected in whole peripheral blood.Treatment of manifestations: Because large prospective trials are lacking, the therapeutic management of individuals with VEXAS syndrome is currently poorly standardized and is based on retrospective studies and expert opinion. The two main approaches to treatment are targeting inflammation and targeting the UBA1-mutated hematopoietic population. Targeting inflammation: Because conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, azathioprine, cyclosporine, or cyclophosphamide have no or minimal anecdotal efficacy, glucocorticoids are generally used as a first-line treatment. Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies. Targeting the UBA1-mutated hematopoietic population: Similar to classic MDS without VEXAS syndrome, hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with multidisciplinary care providers. Surveillance: Monitoring existing manifestations, the individual's response to treatment of manifestations, and the emergence of new manifestations requires routinely scheduled follow up with the treating physicians.VEXAS syndrome is an X-linked disorder caused by somatic pathogenic variants in UBA1. To date, all identified pathogenic variants are acquired (i.e., postzygotic) and lineage restricted in the blood. No confirmed occurrences of vertical transmission or sib recurrence have been reported.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

OTOF-related hearing loss is an auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells (IHCs) to the auditory nerve. Thus, newborn hearing screening (NBHS) that relies on otoacoustic emission (OAE) testing, which primarily assesses function of outer hair cells (OHCs), is usually normal, whereas hearing tests that rely on auditory brain stem response (ABR) testing are abnormal given the failure of signal transmission from IHCs to the auditory nerve. All individuals with OTOF-related hearing loss have severely impaired speech discrimination. The two phenotypes comprising OTOF-related hearing loss are typical OTOF-related hearing loss and atypical OTOF-related hearing loss. Typical OTOF-related hearing loss is characterized by congenital or prelingual, typically severe-to-profound bilateral hearing loss (70 to ≥90 dB) associated with normal OAEs and abnormal ABRs. With age, OAEs decrease or disappear in 20%-80% of individuals. Atypical OTOF-related hearing loss is characterized by either temperature-sensitive OTOF-related hearing loss or progressive OTOF-related hearing loss. Temperature-sensitive OTOF-related hearing loss is characterized by hearing that ranges from normal hearing to moderate hearing loss (0-55 dB) at baseline body temperature and declines to bilateral hearing loss ranging from severe (71-90 dB) to profound (>90 dB) with an elevation of body temperature (approximately 0.5 °C or more). The increased hearing loss resolves typically within hours of baseline body temperature returning to normal. Progressive OTOF-related hearing loss ranges from mild to moderate at onset, and over the course of a few months or years could progress to profound. Rate of hearing loss progression is variable.The diagnosis of OTOF-related hearing loss is established in a proband with suggestive findings and biallelic pathogenic variants in OTOF identified by molecular genetic testing.Treatment of manifestations: There is no cure for OTOF-related hearing loss. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss. While hearing aids may be trialed in persons with mild-to-severe hearing loss, these are unlikely to be beneficial due to auditory synaptopathy being the underlying cause. In contrast, cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. Educational and early intervention programs designed for individuals with hearing loss should start as early as possible. For individuals with atypical temperature-sensitive OTOF-related hearing loss, prevent febrile episodes and avoid exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible. Surveillance: To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time. Agents/circumstances to avoid: For individuals with temperature-sensitive OTOF-related hearing loss, prevent fevers and other activities/ambient conditions that would cause body temperature to rise. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the OTOF pathogenic variants found in the proband so that appropriate early support and management can be provided to the child and family.OTOF-related hearing loss is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an OTOF pathogenic variant, each sib of an affected individual has at conception a 25% chance of having OTOF-related hearing loss, a 50% chance of being a carrier and not having OTOF-related hearing loss, and a 25% chance of not being a carrier and not having OTOF-related hearing loss. Once the pathogenic variants have been identified in a family member with OTOF-related hearing loss, prenatal and preimplantation genetic testing for OTOF-related hearing loss are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a "splenic sequestration." The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections, primarily encapsulated organisms. Acute chest syndrome (ACS) is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation as well as activating pathways that contribute to the pathophysiology directly. Individuals with the highest rates of hemolysis are at higher risk for pulmonary artery hypertension, priapism, and leg ulcers and may be relatively protected from vaso-occlusive pain.SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for the majority of SCD. Other forms of SCD result from compound heterozygosity for HbS with other specific pathogenic beta globin chain variants (e.g., sickle-hemoglobin C disease [Hb S/C], sickle beta-thalassemia [Hb S/β+-thalassemia and Hb S/β0-thalassemia], Hb S/D, Hb S/OArab, Hb S/E). The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal beta globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants including at least one p.Glu6Val allele (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing. Newborn screening for SCD began in the United States in 1975 in New York and expanded to include all 50 states by 2006. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. Some newborn screening programs confirm results with molecular testing.Targeted therapies: Disease-modulating pharmacotherapies (hydroxyurea, L-glutamine, and crizanlizumab); hematopoietic stem cell transplantation; gene therapy. Supportive care: Education of parents, caregivers, and affected individuals on avoidance of potential triggers of vaso-occlusion (dehydration, climate extremes, overexertion, and, when possible, trauma and infection), health maintenance, prophylactic medications, early interventions, warning signs of acute illness, pain management options, and urgent care plan; antibiotic prophylaxis for Streptococcus pneumoniæ; immunizations including those for asplenic individuals; folic acid supplementation; red blood cell (RBC) transfusion therapy and treatment for iron overload. Management of pain episodes includes reversal of inciting triggers, hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodal approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). RBC transfusion as needed for splenic sequestration; splenectomy may be necessary. Fever and suspected infection are treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe ACS, stroke, aplastic crisis, chronic kidney failure) are often treated with RBC transfusion or RBC exchange. Treatment of pulmonary hypertension generally includes treating inciting factors and optimizing SCD therapy to stop progression; severe priapism may require aspiration and irrigation. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for those with kidney disease with kidney transplant for end-stage kidney disease; mental health therapy and community resources. Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual complete blood count with differential and reticulocyte count; annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β0-thalassemia; annual developmental assessment throughout childhood; neurocognitive assessment prior to school entry and as needed; brain MRI in childhood when examination can be tolerated without anesthesia and repeated as needed; annual assessment of vitamin D level and kidney function (blood urea nitrogen, serum creatinine, urinalysis, and urine microalbumin or urine protein-to-creatinine ratio); ophthalmologic evaluation annually beginning at age ten years. Because of the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, six-minute walk test, N-terminal pro-brain natriuretic peptide (NT-proBNP), and sleep study in individuals of any age with cardiac or pulmonary concerns; EKG in those on medications that may alter corrected QT interval; growth assessments throughout childhood; annual assessment of iron status and liver function; MRI as needed to evaluate for iron overload; assessment of mental health and social needs at least annually. Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, trauma, infection, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine. Evaluation of relatives at risk: Early diagnosis of at-risk family members allows for genetic counseling as well as education and intervention before symptoms or end-organ damage are present. Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician. Increased risk for preterm labor, thrombosis, preeclampsia, infectious complications, ACS, and acute painful episodes have been reported during pregnancy. Hydroxyurea should be discontinued during pregnancy.SCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic beta globin chain variants and being affected, a 50% chance of inheriting one beta globin chain variant and being heterozygous, and a 25% chance of inheriting neither of the familial beta globin chain variants. If the SCD-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are heterozygous; if only one (or neither) SCD-related HBB pathogenic variant in a family is known, HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when both HBB pathogenic variants have been identified in an affected family member and the genetic status of the parents is known.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported. APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2.The clinical diagnosis of APDS can be established in a proband based on suggestive clinical findings, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in PIK3CD (for APDS1) or PIK3R1 (for APDS2) identified by molecular genetic testing.Targeted therapies: Leniolisib, a selective PI3K delta (PI3Kδ) inhibitor, has shown promise in clinical trials by directly targeting the overactive PI3Kδ signaling pathway, a hallmark of the condition, and is therefore recommended as a first-line treatment of significant lymphoproliferative disease, including lymphadenopathy and splenomegaly. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is recommended for individuals with lymphoproliferative disease or organomegaly when leniolisib is unavailable; it is also used off-label due to its immunosuppressive and antiproliferative properties. Allogenic hematopoietic stem cell transplant (HSCT) is reserved for individuals with severe or treatment-refractory APDS, including progressive organ damage, recurrent refractory infections, or severe immune dysregulation unresponsive to pharmacologic therapy. Supportive care: Regular intravenous or subcutaneous immunoglobulin replacement therapy to prevent recurrent bacterial infections and improve immune function; long-term prophylactic antibiotics can be considered to reduce the frequency of bacterial infections; individuals with recurrent herpes simplex or herpes zoster virus can receive prophylactic acyclovir or valganciclovir. Leniolisib or sirolimus targeted therapies for lymphoproliferation. Glucocorticoids for acute management of autoimmune complications; other immunosuppressive agents for chronic management of autoimmune manifestations. Bronchodilators and inhaled steroids for chronic lung disease; pulmonary hygiene and preventative pulmonary care to decrease risk of respiratory infections. Nutritional support and dietary modifications for gastrointestinal manifestations; anti-inflammatory medications including high-dose glucocorticoids for treatment of inflammatory bowel disease (which may also improve gut function and enhance absorption of targeted therapies); consider assisted enteral/parenteral nutrition for severe cases. Developmental interventions and educational support to address developmental delays and cognitive impairments. Offer counseling to address psychosocial impacts. Surveillance: Annually assess infection risk (blood/sputum cultures for EBV, CMV, and HSV), immune function (immunoglobulin levels, CD4+, CD8+, B-cell subsets, response to vaccines), lymphoproliferative status (CBC, B-cell counts), autoimmunity (ANA screen, TSH, TPO), respiratory function (including pulmonary function tests), and gastrointestinal status (liver function tests); CT or MRI of the chest every three to five years; colonoscopy symptomatically as needed; liver ultrasound at baseline and every two to three years; psychiatric assessments as needed. Evaluation of relatives at risk: Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluations to assess for possible clinical features related to APDS is recommended for family members found to have an APDS pathogenic variant.APDS is an autosomal dominant disorder. Approximately 80% of individuals diagnosed with APDS have an affected parent and 20% of individuals have the disorder as the result of a de novo PIK3CD gain-of-function variant (for APDS1) or de novo PIK3R1 loss-of-function variant (for APDS2). Once the PIK3CD or PIK3R1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by (1) combined immunodeficiency and (2) terminal hepatic lobular vascular occlusion and hepatic fibrosis manifesting as hepatomegaly and/or hepatic failure. Onset is usually before age six months. The immunodeficiency comprises severe hypogammaglobulinemia, clinical evidence of T-cell immunodeficiency with normal numbers of circulating T and B cells, absent lymph node germinal centers, and absent tissue plasma cells. Bacterial and opportunistic infections including Pneumocystis jirovecii infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur. In the past the prognosis for affected individuals was poor, with 100% mortality in the first year of life if unrecognized and untreated with intravenous or subcutaneous immunoglobulin (IVIG/SCIG) and Pneumocystis jirovecii prophylaxis. However, with early recognition and treatment, including the more recent use of defibrotide, there is a marked improvement in prognosis. Early hematopoietic stem cell transplantation (HSCT) using non-hepatoxic drugs in conditioning and prophylactic defibrotide is potentially curative.The diagnosis of VODI is established in a proband who meets clinical diagnostic criteria or by identification of biallelic pathogenic variants in SP110 on molecular genetic testing.Targeted therapies: IVIG/SCIG; defibrotide for acute hepatic disease; HSCT with non-hepatotoxic conditioning therapy, preferably with defibrotide prophylaxis. Supportive care:Pneumocystis jirovecii prophylaxis; prompt treatment of infections with antibacterials, antivirals, or antifungals as indicated; standard treatment for complications of liver disease; consider liver transplantation, although rate of complications may be high. Surveillance: Assess growth every three to six months; measurement of immunoglobulin concentrations every three to six months; bronchoalveolar lavage to diagnose Pneumocystis jirovecii infection; viral and bacterial cultures and PCR as needed; serum aminotransferases, bilirubin, albumin, complete blood count, and platelet count every three to six months; pulmonary function studies annually once able to perform reliably; cerebrospinal imaging to identify leukodystrophy or other central nervous system pathology when clinically indicated. Agents/circumstances to avoid: Agents known to predispose to hepatic veno-occlusive disease including cyclophosphamide and Senecio alkaloids / bush teas. Evaluation of relatives at risk: If both pathogenic variants in the family are known, it is appropriate to evaluate via molecular genetic testing sibs of a proband who are younger than age 12 months in order to identify those who would benefit from initiation of IVIG or SCIG treatment, Pneumocystis jirovecii prophylaxis, and consideration of preemptive HSCT.VODI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SP110 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SP110 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for VODI are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal greater than distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of the disease.The diagnosis of SMA is established in a proband with a history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, evidence of motor unit disease, and/or biallelic pathogenic variants in SMN1 identified by molecular genetic testing. Increases in SMN2 copy number often modify the phenotype.Targeted therapies: Therapies targeted to the underlying disease mechanism include risdiplam (Evrysdi®; SMN2-directed RNA splicing modifier), nusinersen (Spinraza®; antisense oligonucleotide), and onasemnogene abeparvovec-xioi (Zolgensma®; gene replacement therapy) for the treatment of all types of SMA. Treatment with an SMA-specific disease-modifying treatment is most efficacious when initiated presymptomatically. The FDA has issued a black box warning about Zolgensma®, noting the possibility of serious liver injury and acute liver failure; close monitoring of liver function prior to and in the months following infusion is indicated. These targeted treatments may prevent the development or slow the progression of some features of SMA. New phenotypes in treated individuals are arising, and long-term effects of these treatments are unknown. Supportive care: Proactive supportive treatment by a multidisciplinary team is essential to reduce symptom severity, particularly in the most severe cases of SMA and/or in untreated individuals. When nutrition or dysphagia is a concern, placement of a gastrostomy tube early in the course of the disease is appropriate. Standard therapy for gastroesophageal reflux disease and chronic constipation is recommended. Formal consultation and frequent follow up with a pulmonologist familiar with SMA is necessary. As respiratory function deteriorates, tracheotomy or noninvasive respiratory support may be offered. Surgical repair for scoliosis should be considered based on progression of the curvature, pulmonary function, and bone maturity. Surgical intervention for hip dislocation for those with pain may be indicated. Surveillance: Individuals with SMA require monitoring for the development of symptoms to determine appropriate timing to initiate supportive therapies. Surveillance recommendations for potential side effects and new phenotypes associated with the targeted treatments are emerging. Multidisciplinary evaluation every six months or more frequently for weaker children is indicated to assess nutritional state, respiratory function, motor function, and orthopedic status, and to determine appropriate interventions. Agents/circumstances to avoid: Prolonged fasting, particularly in the acutely ill infant with SMA. Evaluation of relatives at risk: It is appropriate to determine the genetic status of younger, apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of disease-modifying treatments. Pregnancy management: Women with SMA may have an increased rate of preterm birth and need for cesarean section compared to unaffected women. Women with SMA may also experience a persistent worsening of their general muscle weakness after delivery, particularly if disease-modifying therapies are discontinued due to pregnancy status. Due to the risk of respiratory failure, it is recommended that women with neuromuscular disorders, including those with SMA, obtain baseline pulmonary function prior to becoming pregnant, with frequent monitoring during pregnancy. There is limited to no data on the effects of disease-modifying treatments on the developing human fetus. However, based on animal models, risdiplam use should be avoided in pregnant women.SMA is inherited in an autosomal recessive manner. Each pregnancy of a couple who have had a child with SMA has an approximately 25% chance of producing an affected child, an approximately 50% chance of producing an asymptomatic carrier, and an approximately 25% chance of producing an unaffected child who is not a carrier. These recurrence risks deviate slightly from the norm for autosomal recessive inheritance because about 2% of affected individuals have a de novoSMN1 pathogenic variant on one allele; in these instances, only one parent is a carrier of an SMN1 variant, and thus the sibs are not at increased risk for SMA. Ideally preconception (but also prenatal) carrier testing for all individuals in the general population and prenatal testing for pregnancies at increased risk are possible if the diagnosis of SMA has either been confirmed by molecular genetic testing in an affected family member and/or if both parents are found to be carriers of SMA on carrier screening testing.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes. Wiskott-Aldrich syndrome usually presents in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; recurrent bacterial, viral, fungal, and/or opportunistic infections; and eczema. Approximately 25%-40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, vasculitis, rheumatoid arthritis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have small platelet volume and thrombocytopenia. Severe disease-related events include severe bleeding episodes (14%), autoimmunity (12%), life-threatening infections (7%), and malignancy (5%). Males with XLN typically have congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities.The diagnosis of a WAS-related disorder is established in a male proband with both congenital thrombocytopenia (<70,000 platelets/mm3) and small platelets; at least one of the following features: eczema, recurrent bacterial, viral, and fungal infections, autoimmune disease(s), malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of a WAS-related disorder; and a hemizygous WAS pathogenic variant identified by molecular genetic testing (necessary to confirm the diagnosis). The diagnosis of a WAS-related disorder in a female is uncommon. It is usually established by identification of a heterozygous pathogenic variant in WAS by molecular genetic testing in a female with severe skewed X-chromosome inactivation and increased expression of the mutated WAS allele.Targeted therapy: The only curative targeted therapy clinically available for Wiskott-Aldrich syndrome is allogeneic hematopoietic stem cell transplantation (HSCT). In those with XLT, decision to treat with HSCT is determined on an individual basis. Treatment of manifestations: In those with Wiskott-Aldrich syndrome and XLT, treatment is individualized based on disease manifestations and includes management of thrombocytopenia; prevention of infection with immunoglobulin replacement; topical steroids for eczema; antibiotics as needed for chronic skin infections; prophylactic antibiotics for Pneumocystis jirovecii in infants with Wiskott-Aldrich syndrome; intravenous immunoglobulin G; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and judicious use of immunosuppressants for autoimmune disease prior to definitive treatment. In those with XLN, treatment includes granulocyte colony-stimulating factor therapy; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and treatment of myelodysplastic syndrome and acute myelogenous leukemia per hematologist/oncologist. Surveillance: Complete blood count including platelet count and size and assessment for complications associated with increased bleeding as recommended by hematologist; annual skin examination; assessment by immunologist including for recurrent infections with frequency as recommended by immunologist; annual clinical assessment for autoimmune dysfunction and for manifestations of lymphoma. Agents/circumstances to avoid: Circumcision of at-risk newborn males who have thrombocytopenia; use of medications that interfere with platelet function. Defer elective procedures until after HSCT. Evaluation of relatives at risk: Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment. Evaluation of relatives considering stem cell donation to inform transplant donor decision making.WAS-related disorders are inherited in an X-linked manner. If the mother of the proband has a WAS pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be symptomatic. Females who inherit the pathogenic variant will be carriers and are typically asymptomatic. Males with a WAS-related disorder transmit the pathogenic variant to all of their daughters and none of their sons. Once the WAS pathogenic variant has been identified in a family member, molecular genetic testing to identify female heterozygotes and prenatal and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited neurodegenerative disorder, involving mainly the white matter and axons of the central nervous system and the adrenal cortex and is a frequent but under-recognized cause of primary adrenocortical insufficiency. X-ALD is caused by a defect in the gene ABCD1 that maps to Xq 28 locus. The primary biochemical disorder is the accumulation of saturated very long chain fatty acids (VLCFA) secondary to peroxisomal dysfunction. The incidence in males is estimated to be 1:14,700 live births, without any difference among different ethnicities. X-ALD presents with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD; however, there is no correlation between X-ALD phenotype and specific mutations in the ABCD1 gene. When suspected, the diagnosis is established biochemically with the gold standard for diagnosis being genetic testing (ABCD1 analysis). Currently, there is no satisfying treatment to prevent the onset or modify the progression of the neurologic or endocrine components of the disease. Allogeneic hematopoietic stem cell (HSC) transplantation is the treatment of choice for individuals with early stages of the cerebral form of the disease. An alternative option for patients without HLA-matched donors is autologous HSC-gene therapy with lentivirally corrected cells. Once adrenal insufficiency is present, hormonal replacement therapy is identical to that of autoimmune Addison’s disease. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.Copyright © 2000-2025, MDText.com, Inc.

The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. At least three clinical types have been suggested in untreated individuals: mild (clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities); moderate (clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities); and severe (obvious progression leading to early death from primary central nervous system involvement or infection). Core features of untreated individuals generally include early childhood-onset non-progressive hearing loss, frequent infections due to immunodeficiency, rheumatologic symptoms (especially systemic lupus erythematosus), developmental delay / intellectual disability, low tone, ataxia, spastic paraplegia, psychiatric findings, bone disease (ranging from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis), gastrointestinal dysfunction (including diarrhea, swallowing issues / aspiration, and enlarged liver and spleen), poor growth, eye issues (including tapetoretinal degeneration and optic nerve atrophy), cardiac complications in adults, and pulmonary issues (including parenchymal lung disease). However, with the advent of enzyme replacement therapy, the natural history of this condition may change. Long-term velmanase alfa (VA) treatment outcomes are still being elucidated, but may include improvement in hearing, immunologic profile, and quality of life (improved clinical outcomes for muscle strength). Similarly, affected individuals who underwent hematopoietic stem cell transplantation (HSCT) experienced improvement in development (with preservation of previously learned skills), ability to participate in activities of daily living, stabilization or improvement in skeletal abnormalities, and improvement in hearing ability, although expressive speech and hearing deficiencies remained the most significant clinical problems after HSCT.The diagnosis of alpha-mannosidosis is established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (typically 5%-10% of normal activity) in leukocytes or other nucleated cells AND/OR by the identification of biallelic pathogenic variants in MAN2B1 by molecular genetic testing.Targeted therapies: Velmanase alfa (Lamzede®) enzyme replacement therapy (ERT) has been very well tolerated and is now regarded as a standard treatment for alpha-mannosidosis; improvement in both biochemical and functional parameters have been reported in treated individuals. Hematopoietic stem cell transplantation (HSCT) has been offered as a treatment for severe alpha-mannosidosis. While HSCT carries risks, the data suggests it is a feasible therapeutic option for alpha-mannosidosis, with better outcomes achieved by performing it early before complications arise, balancing the risks and benefits. Supportive care: Hearing aids may be helpful for those with sensorineural hearing loss, whereas pressure-equalizing tubes may be helpful for those with conductive hearing loss. Consider palmidronate (Aredia®) monthly or zoledronic acid (Aclasta®) once a year for osteoporosis or osteopenia. Standard treatment for immunodeficiency / recurrent infections, systemic lupus erythematosus, communicating hydrocephalus, ataxia / gait abnormalities, poor weight gain / growth issues, eye/vision issues, cardiac valve dysfunction / dilated cardiomyopathy, recurrent chest infections / respiratory dysfunction, developmental delay / intellectual disability, and psychiatric manifestations. Surveillance: At each visit, measure weight, length/height, head circumference, and BMI; monitor growth pattern, developmental progress, and educational needs; assess for depression, including sleep disturbances, anxiety, &/or findings suggestive of psychosis; assess for new manifestations such as ataxia and gait abnormalities; evaluate for asthenia and signs/symptoms of communicating hydrocephalus; assess for muscle pain, joint aches, reduced range of motion, and bone pain; monitor for diarrhea and for size of the liver and spleen; and assess for the number and type of infections. Every six to 12 months in childhood and annually in adults, assess fine motor function, gross motor function, endurance, and muscle strength and tone by physical therapy; and assess for features of ataxia. Every one to two years, or as clinically indicated in those with hearing aids, perform an audiology evaluation. Every two to five years in children, adolescents, and adults, consider DXA bone densitometry scan to assess for osteopenia or osteoporosis; radiographs of the hips/spine may be indicated. Annually (or as clinically indicated), routine biochemical lab assessment to include liver and kidney health, blood glucose levels, fluid and electrolyte balance, and complete blood count (with platelets); consider immunlobulin levels, ESR and C-reactive protein; pulmonary function tests; and ophthalmology evaluation. At regular intervals based on clinical features, consider endocrinology evaluations, including hormonal and lipid profiles; consider assessment of liver and spleen size through ultrasound or MRI imaging; consider electrocardiogram, 24-hour electrocardiogram, and echocardiogram; consider sleep study. For those on ERT, plasma oligosaccharides to assess treatment response as clinically indicated. Post-HSCT evaluation of standard surveillance per hematologist/oncologist, which may include ongoing assessment for chimerism and enzyme activity if indicated. Evaluation of relatives at risk: Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis. Evaluations can include molecular genetic testing if the pathogenic variants in the family are known or assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.Alpha-mannosidosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible by assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing once the pathogenic variants have been identified in the family.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D), is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including the bone marrow, liver, spleen, and brain. Familial HLH usually presents as an acute illness with prolonged and high fever, cytopenias, and hepatosplenomegaly. Rash and lymphadenopathy are less common. Individuals with fHLH may also exhibit liver dysfunction and neurologic abnormalities. Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero, symptomatic presentation can occur throughout childhood and into adulthood. Median survival in untreated infants with fHLH who develop active disease is less than two months after onset of manifestations; progressive manifestations of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths. However, the use of newer chemoimmunotherapy protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival.The diagnosis of fHLH is established in a proband with suggestive findings by identification of either biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D) or (rarely) a gain-of-function heterozygous variant in STXBP2.Targeted therapies: Treatment regimens focus on use of chemoimmunotherapy to treat active disease followed by allogeneic HSCT, the only curative therapy. Etoposide-containing regimens such as HLH-94 and HLH-2004, followed by allogeneic HSCT, are typically used. A regimen that includes anti-interferon-gamma antibody (emapalumab) is FDA approved for the treatment of children and adults with relapsed or refractory HLH or intolerance of conventional therapies. Supportive care: Management should be coordinated by or in consultation with a multidisciplinary team with expertise in fHLH, including specialists in hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics. Supportive care that should accompany treatment with chemoimmunotherapy and allogenic HSCT includes antibiotics or antiviral agents to treat or prevent infections, and antipyretics, intravenous fluids, electrolyte replacement, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma, and/or cryoprecipitate. Surveillance: Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement; thus, surveillance focuses on potential complications of fHLH while fHLH is active, such as bleeding, hypotension, respiratory distress, neurologic complications, malnutrition, infection, liver, or other organ failure. Agents/circumstances to avoid: Live vaccines; exposure to infections; acetaminophen in persons with liver failure; nonsteroidal anti-inflammatory drugs in persons with thrombocytopenia; areas of construction or soil manipulation (which increase the risk for fungal infection in individuals with neutropenia); transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT. Evaluation of relatives at risk: It is appropriate to identify – before symptoms occur –those at-risk sibs who have the family-specific pathogenic variants so that they can be monitored and preemptive HSCT considered (particularly during febrile episodes) for development of manifestations of active disease. Any manifestations of possible active disease should prompt more detailed evaluation and referral to a clinician with expertise in fHLH.Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of STXBP2-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.) If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Once the fHLH-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem. Often congenital contractures and/or fractures are present. Intellect is normal. Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement.The diagnosis of X-linked infantile spinal muscular atrophy is established in a male proband with suggestive clinical features and a hemizygous pathogenic variant in UBA1 identified by molecular genetic testing.Treatment of manifestations: Assure adequate caloric intake by caloric supplementation and/or gastrostomy feedings; manage constipation with diet or medication; provide rigorous airway clearance techniques, secretion management, and, ideally, noninvasive ventilatory support, although tracheostomy with permanent mechanical ventilation can be considered; discuss "do not attempt to resuscitate" status with the family before respiratory failure occurs. Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis. Standard treatment for gastroesophageal reflux disease. Surveillance: Affected children should be followed at least monthly until the severity and disease course are more clearly delineated. Routine evaluations by a multidisciplinary team, including neurology, pulmonology, orthopedics, physical and occupational therapy, nutrition, and gastroenterology, as needed. Measurement of growth parameters, neurologic evaluation, nutrition/feeding assessment, evaluation of respiratory status, and physical examination for kyphosis/scoliosis at each visit.By definition, XL-SMA is inherited in an X-linked manner. Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. Once the UBA1 pathogenic variant has been identified in an affected family member, carrier testing for at risk female relatives and prenatal and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile, juvenile, and adult MLD. The age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD: Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. Language, cognitive, and gross and fine motor skills regress as the disease progresses. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD: Onset is between age 30 months and 16 years. Initial manifestations include a decline in school performance and the emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD: Onset occurs after the age of 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures predominate initially. Peripheral neuropathy is common. The disease course is variable, with periods of stability interspersed with periods of decline, and may extend over two to three decades. The final stage is similar to earlier-onset forms.The diagnosis of MLD is established in a proband with the suggestive findings of progressive neurologic dysfunction, brain MRI evidence of leukodystrophy, or arylsulfatase A enzyme deficiency by identification of biallelic ARSA pathogenic variants on molecular genetic testing, elevated urinary excretion of sulfatides, or – less commonly – metachromatic lipid deposits in nervous system tissue.Targeted therapy: Allogeneic hematopoietic stem cell transplantation (HSCT) can treat primary central nervous system manifestations in those with pre- and very early-symptomatic juvenile- or adult-onset MLD. Autologous HSCT using gene-modified hematopoietic stem cells (also known as ex vivo gene therapy) is approved in the United States, European Union, and United Kingdom for individuals with presymptomatic late-infantile MLD, presymptomatic early-onset juvenile MLD, or early-symptomatic early-onset juvenile MLD with maintained ability to walk and before the onset of cognitive decline. Supportive care: Developmental and educational support. Treatment per orthopedist, physical medicine and rehabilitation, and physical and occupational therapists to avoid contractures and falls and maintain neuromuscular function and mobility, muscle relaxants for contractures, and safety measures for gait or movement limitations. Feeding therapy, swallowing aids, suction equipment, and other standard treatments for drooling, swallowing difficulty, and gastroesophageal reflux. Gastrostomy tube as needed for feeding. Treatment of seizures using anti-seizure medications in standard protocols. Standard treatments for impaired vison and/or hearing and respiratory issues. Family support to enable parents and/or caregivers to anticipate decisions on walking aids, wheelchairs, feeding tubes, and other changing care needs. Surveillance: Brain MRI examination to monitor the status of demyelination using MLD brain MRI severity scoring with frequency per neurologist. Assess motor function and support needs using gross motor function measurement (GMFM). Monitor for disease exacerbations following febrile infections. At each visit, assess physical mobility, self-help skills, development, neurobehavioral and psychiatric issues, growth, nutrition, safety of oral intake, need for feeding support, constipation, respiratory issues, and family needs. Vision and hearing assessment as needed.MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe "delayed" or "late-onset" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals). Some healthy individuals who are deficient in red blood cell ADA (termed "partial ADA deficiency") have been discovered by screening populations or relatives of individuals with ADA-SCID. Newborn screening (NBS) for SCID uses extracts from Guthrie card dried blood spots to measure T-cell receptor excision circle (TREC) DNA by polymerase chain reaction (PCR). Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS). Both techniques can identify ADA-SCID before affected infants become symptomatic. Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia. Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID. Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function. If immune function is not restored with enzyme replacement therapy (ERT), gene therapy, or hematopoietic stem cell transplantation (HSCT), children with ADA-SCID rarely survive beyond age one to two years. NBS for SCID does not identify individuals with the ADA-CID phenotype whose TREC numbers are above the threshold values of most screening laboratories. However, ADA-CID is identified by TMS NBS since the ADA substrates Ado and dAdo are increased. As TMS NBS for Ado/dAdo is not yet widely performed, individuals with ADA-CID are more often clinically diagnosed between ages one and ten years ("delayed" onset), or less often in the second to fourth decades ("late"/"adult" onset). Because the immunologic abnormalities are less pronounced than those of ADA-SCID, infections in ADA-CID may not be life-threatening and include recurrent otitis media, sinusitis, upper respiratory infections, and human papilloma viral infections. Untreated individuals with ADA-CID can develop over time chronic pulmonary disease, autoimmunity, atopic disease with elevated immunoglobulin E, and malignancy.The diagnosis of ADA deficiency is established in a proband with suggestive findings either by biochemical testing showing <1% of ADA catalytic activity in red blood cells or in extracts of dried blood spots (valid in untransfused individuals), or by molecular genetic testing identifying biallelic pathogenic variants in ADA. Frequently, both types of testing are performed.Treatment of manifestations: Newborns with an abnormal NBS result suggestive of ADA-SCID (by either method) require immediate protection from risk factors for infection and referral for a subspecialty immunology evaluation at a center with expertise in both diagnosis of SCID and its genetic causes and SCID treatment protocols. Symptomatic treatment involves treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against Pneumocystis jirovecii pneumonia (formerly Pneumocystis carinii) and fungal infections. Prophylaxis against viral infections depends upon exposure and requires frequent surveillance via viral PCR-based testing, with appropriate targeted virus-specific therapy if present. Targeted therapies: Correcting the ADA deficiency either systemically or selectively in lymphoid cells employs one of three options: (1) enzyme replacement therapy (ERT) by intramuscular administration of PEGylated ADA, (2) allogeneic HSCT, or (3) autologous hematopoietic stem cell ADA gene therapy (HSC-GT) – the latter two are curative. Often, ERT is initiated first to rapidly correct the metabolic defect and to protect against serious infections as well as neurologic/behavioral abnormalities. It is discontinued at the time HSCT or HSC-GT is performed. Surveillance: The following evaluations are recommended to monitor existing and emerging clinical manifestations and the response to targeted treatment and supportive care: (1) absolute lymphocyte subset counts (T, B, NK cells), quantitative serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function; (2) total red blood cell deoxyadenosine nucleotides (dAXP) and, if on ERT, plasma ADA activity; and (3) screening for Epstein-Bar virus (EBV)-related lymphoma or other lymphomas after age three years, particularly when lymphocyte counts are declining while on prolonged ERT. Agents/circumstances to avoid: To ensure the safety of the infant/older individual with ADA deficiency while treatment to achieve immunocompetence is pending, parents and other care providers need to avoid the following risks of infection: (1) breastfeeding and breast milk until maternal CMV status is established by CMV serologies; (2) exposure to young children, sick contacts, individuals with cold sores, crowded enclosed spaces, and sources of aerosolized fungal spores such as areas of construction or soil manipulation; (3) live viral vaccines for the affected infant as well as household contacts; and (4) transfusion of non-irradiated blood products. Medications to avoid include adenine arabinoside, a substrate for ADA, as an antiviral agent and/or as chemotherapy of malignancies; and pentostatin, a potent ADA inhibitor used to treat some lymphoid malignancies, which would be ineffective in persons with ADA deficiency and would interfere with PEGylated ADA. Evaluation of relatives at risk: In an at-risk fetus, when the ADA pathogenic variants causing ADA-SCID in the family are known, prenatal genetic testing may be performed to help prepare for optimal management of an affected infant at birth (i.e., identification of a center with expertise in SCID treatment protocols that can help initiate ERT and the search for an HSCT donor and explain ways to ensure the safety of the infant while awaiting HSCT). If prenatal testing has not been performed, an at-risk newborn clinically suspected of SCID should immediately be placed in an appropriate environment to reduce the risk of infection, and the following testing should be performed before administration of a blood transfusion to allow earliest possible diagnosis and initiation of treatment: identification of the ADA pathogenic variants and measurement of ADA catalytic activity and level of dAXP in red blood cells.Therapies under investigation: Various approaches to HSC-GT are under investigation.ADA deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ADA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. An individual who inherits two pathogenic ADA variants will have either ADA-SCID or a delayed or late-onset ADA-CID phenotype that correlates with the least severe ADA pathogenic variant inherited. Once the ADA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and β-thalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain). Individuals with β-thalassemia major present between ages six and 24 months with pallor due to severe anemia, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly. Feeding problems, diarrhea, irritability, and recurrent bouts of fever may occur. Treatment with regular red blood cell transfusions and iron chelation therapy allows for normal growth and development and improves prognosis. Long-term complications associated with iron overload include stunted growth, dilated cardiomyopathy, liver disease, and endocrinopathies. Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Additional clinical features may include jaundice, cholelithiasis, hepatosplenomegaly, skeletal changes (long bone deformities, characteristic craniofacial features, and osteoporosis), leg ulcers, pulmonary hypertension, extramedullary masses of hyperplastic erythroid marrow, and increased risk of thrombotic complications. Individuals with β-thalassemia intermedia are at risk for iron overload secondary to increased intestinal absorption of iron as a result of dysregulation of iron metabolism caused by ineffective erythropoiesis.The diagnosis of β-thalassemia is established in a proband older than age 12 months by identification of microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and decreased or complete absence of hemoglobin A (HbA) and increased hemoglobin A2 (HbA2) and often hemoglobin F (HbF) on hemoglobin analysis. Identification of biallelic pathogenic variants in HBB on molecular genetic testing can establish the diagnosis in individuals younger than age 12 months who have a positive or suggestive newborn screening result and/or unexplained microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear.Targeted therapies: For β-thalassemia major, hematopoietic stem cell transplantation (HSCT), cord blood transplantation from a related donor, or autologous HSCT with gene therapy. Supportive care: For β-thalassemia major, regular red blood cell transfusions with iron chelation therapy (e.g., deferoxamine B, deferiprone, deferasirox). Transfusion requirements may be reduced with the use of luspatercept. Anticoagulation for unprovoked venous thromboembolism; cholecystectomy for biliary colic; additional treatments for osteoporosis include hormone replacement therapy, vitamin D supplementation, regular physical activity, and bisphosphonates. For β-thalassemia intermedia, splenectomy, folic acid supplementation, red blood cell transfusions as needed, and iron chelation. Some individuals can benefit from HbF induction with hydroxyurea. Luspatercept may also be used to ameliorate anemia with variable efficacy. Cholecystectomy for biliary colic; vitamin D supplementation, regular physical activity, and bisphosphonates for osteoporosis; referral for treatment of pulmonary hypertension; anticoagulation for unprovoked venous thromboembolism. Surveillance: For β-thalassemia major, complete blood count every three to four weeks and with illnesses. For β-thalassemia intermedia, complete blood count every three to four months and with illnesses. Additional surveillance in individuals with β-thalassemia major and β-thalassemia intermedia: monitor efficacy and side effects of transfusion therapy and chelation therapy with monthly physical examination; evaluation of growth and development every three months during childhood; ALT and serum ferritin every three months; annual evaluation of eyes, hearing, heart, endocrine function (thyroid, endocrine pancreas, parathyroid, adrenal, pituitary), and myocardial and liver MRI. In adults: bone densitometry to assess for osteoporosis; serum alpha-fetoprotein concentration for early detection of hepatocarcinoma in those with hepatitis C and iron overload. Agents/circumstances to avoid: Alcohol consumption if there is history of liver damage, iron-containing preparations, and exposure to infection. Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk sibs should be offered to allow for early diagnosis and treatment. Hematologic testing can be used if the pathogenic variants in the family are not known. Pregnancy management: Individuals with β-thalassemia major often require increased red blood cell transfusions during pregnancy. Individuals with β-thalassemia intermedia often have a significant drop in hemoglobin necessitating regular red blood cell transfusions during pregnancy, and those who have never received a red blood cell transfusion or who received minimal transfusions are at risk for severe alloimmune anemia if red blood cell transfusions are required during pregnancy. Iron chelation should not be given during fetal organogenesis and may be started in the second trimester if necessary due to extent of maternal iron overload. Cardiac evaluation including pulmonary hypertension screening is recommended prior to conception.Beta-thalassemia major and β-thalassemia intermedia are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a (typically) asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If one parent is known to be heterozygous for an HBB pathogenic variant and the other parent is affected with β-thalassemia, each sib of an affected individual has a 50% chance of inheriting biallelic HBB pathogenic variants and being affected and a 50% chance of inheriting one HBB pathogenic variant and being a (typically) asymptomatic carrier. Carrier testing for at-risk relatives can be done by hematologic and/or molecular genetic testing (if the familial pathogenic variants are known). Once both HBB pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is characterized by systemic autoimmunity, typically beginning in the first year of life, which includes the triad of enteropathy (manifesting as malabsorption and watery diarrhea), endocrinopathy (most commonly type 1 insulin-dependent diabetes mellitus), and eczematous dermatitis. In addition to these manifestations, many children have other autoimmune phenomena including cytopenias, autoimmune hepatitis, nephropathy, lymphadenopathy, splenomegaly, alopecia, arthritis, and interstitial lung disease related to immune dysregulation. Fetal presentation of IPEX syndrome includes hydrops, echogenic bowel, skin desquamation, intrauterine growth deficiency, and fetal akinesia. Without aggressive immunosuppression or hematopoietic stem cell transplantation (HSCT), the majority of affected males will die within the first one to two years of life from metabolic derangements, severe malabsorption, or sepsis. Individuals with a milder phenotype have survived into the second or third decade of life, but this is uncommon.The diagnosis is established in a male proband with typical clinical findings, absent regulatory T cells (Treg) in blood or tissues, decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry (although FOXP3 levels in Treg can be normal in some individuals), and a hemizygous pathogenic variant in FOXP3 identified by molecular genetic testing. Heterozygous females have not been reported to have clinical findings typical of IPEX syndrome.Targeted therapies: HSCT offers the only potential cure for IPEX syndrome. T cell-directed immune suppression can include either an mTOR inhibitor (sirolimus) or calcineurin inhibitor (cyclosporin A or tacrolimus), alone or in combination with corticosteroids. Supportive care: Total parenteral nutrition (TPN) with fluids and electrolyte support is needed until intestinal function can be established with immune suppression. Treatment of type 1 insulin-dependent diabetes mellitus with insulin and carbohydrate management is standard, as is management of autoimmune thyroid disease. Skin conditions are managed with topical therapies, which can include steroids, tacrolimus, and emollients. Autoimmune neutropenia has been successfully treated with granulocyte colony-stimulating factor; pemphigus nodularis has been treated with rituximab (anti-CD20), and rituximab has been used for other autoantibody-mediated disease. Prophylactic antibiotic therapy may be required for autoimmune neutropenia or recurrent infections with central venous access and TPN. Aggressive management of dermatitis with topical steroids and anti-inflammatory agents as needed to prevent cutaneous infections. Surveillance: Monitor growth, nutritional intake, and stooling patterns at each visit; glucose tolerance test, hemoglobin A1c, and thyroid function tests every three to six months; skin exam at each visit; complete blood count, blood urea nitrogen, creatinine, urinalysis, and serum aspartate transaminase and alanine transaminase every three to six months. Agents/circumstances to avoid: Withhold immunizations until after HSCT, if possible. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk males either prenatally or immediately after birth to enable early diagnosis and HSCT and/or immune suppression treatment in affected males before significant organ damage occurs.IPEX syndrome is inherited in an X-linked manner. The risk to sibs of the proband depends on the genetic status of the mother. If the mother of the proband has a FOXP3 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous (to date, IPEX syndrome has not been reported in females who are heterozygous for a FOXP3 pathogenic variant). Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Once the FOXP3 pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal/preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity. Type 1GD is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and the absence of primary central nervous system disease. Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years. Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.The diagnosis of GD relies on demonstration of deficient glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral blood leukocytes or other nucleated cells, or by the identification of biallelic pathogenic variants in GBA1 on molecular genetic testing.Targeted therapy: Options include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT; e.g., miglustat, eliglustat). Hematopoietic stem cell transplantation may be an option in individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD). Supportive care: When possible, management by a multidisciplinary team at a GD Comprehensive Treatment Center. Symptomatic treatment includes partial or total splenectomy for those with massive splenomegaly, significant areas of splenic fibrosis, and persistent significant thrombocytopenia (platelets <30,000/mm3) with a risk of bleeding; splenectomy may be needed even in those on targeted therapy. Supportive care for all affected individuals may include: orthopedic management of bone disease; analgesics for bone pain; joint replacement surgery for relief from chronic pain and restoration of function; anti-bone resorptive agents, calcium, and vitamin D for osteoporosis; transfusion of blood products for severe anemia and bleeding; the use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding; treatment of cholelithiasis, pulmonary disease, pulmonary hypertension, multiple myeloma, psychological manifestations, parkinsonism, and seizures according to the relevant specialist; social work support and care coordination as needed. Surveillance: Clinical assessment of disease progression at least every six months to include hematologic, orthopedic, pulmonary, cardiac, psychiatric, and neurologic assessment; clinical assessment for abdominal pain, early satiety, evidence of bleeding diathesis, growth and weight gain, clinical disease markers, and liver enzymes; imaging for spleen and liver volumes at least every one to two years. Additional evaluations to be done as needed include radiographs, MRI, and dual-energy x-ray absorptiometry (DXA) scan; bone age in children with growth and pubertal delay; ultrasound for gallstones; serum iron, ferritin, and vitamin B12 in those with anemia; and EKG and echocardiography with Doppler in individuals after splenectomy and those with elevated pulmonary artery pressure. Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs in individuals with moderate-to-severe thrombocytopenia. Evaluation of relatives at risk: It is appropriate to offer testing to asymptomatic at-risk relatives so that those with glucocerebrosidase enzyme deficiency or biallelic pathogenic variants can benefit from early diagnosis and treatment if indicated. Pregnancy management: Pregnancy can exacerbate preexisting symptoms and trigger new features in affected women. Those with severe thrombocytopenia and/or clotting abnormalities are at increased risk for bleeding around the time of delivery. Evaluation by a hematologist prior to delivery is recommended. The lack of studies on the safety of eliglustat use during pregnancy and lactation has led to the recommendation that this medication be avoided during pregnancy, if possible.GD is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygous for a GBA1 pathogenic variant; in some families, an asymptomatic parent may be found to be homozygous rather than heterozygous. If both parents are known to be heterozygous for a GBA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial GBA1 pathogenic variants. Once the GBA1 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk family members, preimplantation genetic testing, and prenatal testing for GD are possible. The identification of 0%-15% of normal glucocerebrosidase enzyme activity in fetal samples obtained by chorionic villus sampling (CVS) or amniocentesis – ideally complemented by molecular genetic testing – can also be used to establish affected status in a fetus.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).The diagnosis of NBS is established in a proband with characteristic clinical features and biallelic pathogenic variants in NBN on molecular genetic testing and/or absent nibrin protein on immunoblotting assay.Treatment of manifestations: Standard antimicrobial therapies for infections; immunoglobulin replacement therapy in individuals with severe hypogammaglobulinemia and frequent infections; acellular vaccines; standard treatment of bronchiectasis and pulmonary infections; chemotherapy protocols for lymphoid malignancies adapted to individual tolerance; treatment of solid tumors adapted to individual tolerance; consideration of hematopoietic stem cell transplantation; hormone replacement therapy for females who have hypergonadotropic hypogonadism. Surveillance: For affected individuals. Periodic follow up to monitor physical growth, infection frequency, and developmental progress; lifelong monitoring of immune biomarkers; monitor for malignancy and particularly in those with weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, and hepatosplenomegaly (assessment should be considered using ultrasonography, MRI, biopsy); monitor pubertal progression in both sexes and for premature ovarian insufficiency in females; monthly breast self-examination when hormone replacement therapy is administered; assess cognitive developmental and intellectual abilities before starting school and follow up periodically. For heterozygous adults. Monitor for malignancy, particularly breast cancer in women and prostate cancer in men. Agents/circumstances to avoid: Because the cells from individuals with NBS are radiosensitive in vitro, doses of radiation used in radiotherapy need to be reduced. Unnecessary exposure to imaging studies that use ionizing radiation (plain radiograph, CT scan) should be avoided and use of MRI and/or ultrasound considered. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given. Evaluation of relatives at risk: It is appropriate to offer molecular genetic testing for the familial NBN pathogenic variants to apparently asymptomatic adult relatives of an affected individual in order to identify family members who are heterozygous for an NBN pathogenic variant and would benefit from monitoring for malignancy.NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial NBN pathogenic variants. Heterozygotes are not at risk for NBS. However, heterozygous NBN pathogenic variants may be associated with an increased risk for breast cancer in women and prostate cancer in men. Carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) comprise overlapping clinical phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. KSS is a progressive multisystem disorder with onset before age 20 years characterized by pigmentary retinopathy, CPEO, and cardiac conduction abnormality. Additional features can include cerebellar ataxia, tremor, intellectual disability or cognitive decline, dementia, sensorineural hearing loss, oropharyngeal and esophageal dysfunction, exercise intolerance, muscle weakness, and endocrinopathies. Brain imaging typically shows bilateral lesions in the globus pallidus and white matter. KSS spectrum includes individuals with KSS in addition to individuals with ptosis and/or ophthalmoparesis and at least one of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, growth deficiency, cognitive impairment, tremor, or cardiomyopathy. Compared to CPEO-plus, individuals with KSS spectrum have more severe muscle involvement (e.g., weakness, atrophy) and overall have a worse prognosis. PS is characterized by pancytopenia (typically transfusion-dependent sideroblastic anemia with variable cell line involvement), exocrine pancreatic dysfunction, poor weight gain, and lactic acidosis. PS manifestations also include renal tubular acidosis, short stature, and elevated liver enzymes. PS may be fatal in infancy due to neutropenia-related infection or refractory metabolic acidosis. CPEO is characterized by ptosis, ophthalmoplegia, oropharyngeal weakness, variable proximal limb weakness, and/or exercise intolerance. CPEO-plus includes CPEO with additional multisystemic involvement including neuropathy, diabetes mellitus, migraines, hypothyroidism, neuropsychiatric manifestations, and optic neuropathy. Rarely, an SLSMDS can manifest as Leigh syndrome, which is characterized as developmental delays, neurodevelopmental regression, lactic acidosis, and bilateral symmetric basal ganglia, brain stem, and/or midbrain lesions on MRI.The diagnosis of an SLSMDS is established in a proband with characteristic clinical features by identification of a mitochondrial DNA (mtDNA) deletion ranging in size from 1.1 to 10 kb on molecular genetic testing. SLSMDSs can be identified in DNA from blood, buccal cells, and urine in affected children; analysis of skeletal muscle tissue may be required to detect an SLSMDS in an affected adult.Targeted therapy: Folinic acid supplementation in individuals with KSS with low 5-methyltetrahydrofolate in CSF or white matter abnormalities on brain MRI. Supportive care: Consider mitochondrial supplement therapies such as coenzyme Q10 and antioxidants; optimize nutrition and exercise regimen to prevent acute decompensation; physical and occupational therapy for myopathy and/or ataxia; standard treatment with anti-seizure medication; hearing aids or cochlear implants for sensorineural hearing loss; developmental and educational support; feeding therapy; consider gastrostomy tube placement if poor weight gain, choking, or aspiration risk is present; dilation of the upper esophageal sphincter to alleviate cricopharyngeal achalasia; prophylactic placement of cardiac pacemaker in individuals with cardiac conduction block, with consideration of an implantable cardioverter defibrillator; hormone replacement therapy per endocrinologist; electrolyte monitoring and replacement for renal tubular acidosis; eyelid slings and/or ptosis repair for severe ptosis; eye ointment for dry eyes; eyeglass prisms for diplopia; transfusion therapy for individuals with PS with sideroblastic anemia; replacement of pancreatic enzymes for exocrine pancreatic insufficiency; ventilatory support for respiratory abnormalities that may occur in individuals with Leigh syndrome; standard treatment of anxiety and/or depression; social work support and care coordination as needed. Surveillance: Annual neurology assessment for ataxia, neuropathy, seizures, and myopathy; annual audiology evaluation; annual assessment of developmental progress, educational needs, and cognitive issues; annual evaluation by a neuro-ophthalmologist and/or retinal specialist and oculoplastics; measurement of growth parameters and evaluation of nutritional status and safety of oral intake at each visit; annual assessment of mobility and self-help skills with physical medicine, occupational therapy, and/or physical therapy; EKG and echocardiogram every six to 12 months; annual assessment with an endocrinologist; BUN and creatinine, with consideration of cystatin C in those with low muscle mass; complete blood count in those with PS to assess transfusion needs with additional labs per hematologist, and ferritin for those needing recurrent transfusions as needed; annual complete blood count in those with other SLSMDSs; fecal fat and fecal elastase as needed based on symptoms; monitor for evidence of aspiration and respiratory insufficiency at each visit; assess family needs at each visit. Agents/circumstances to avoid: Volatile anesthetic hypersensitivity may occur. Avoid prolonged treatment with propofol (>30-60 minutes). Medications should be reviewed with a physician familiar with mitochondrial disorders including a thorough individualized assessment of risk vs benefit as several medications may be toxic to mitochondria.SLSMDSs are almost never inherited, suggesting that these disorders are typically caused by a de novo single large-scale mitochondrial DNA deletion (SLSMD) that occurs in the mother's oocytes during germline development or in the embryo during embryogenesis. If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births). Maternal transmission to more than one child has not been reported to date. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are scientifically possible but technically prohibitive as next-generation sequencing methodology does not accurately quantify heteroplasmy level of an SLSMD and droplet digital quantitative PCR cannot reliably detect less than 10% heteroplasmy levels of an SLSMD. Further, prenatal testing is not clinically available due to the inability to accurately interpret the clinical prognosis based on prenatal diagnostic results of an SLSMD.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.The clinical diagnosis can be established in a proband with macrocytic anemia with onset prior to age one year, no other significant cytopenias, reticulocytopenia, normal marrow cellularity with a paucity of erythroid precursors, and no evidence of another acquired or inherited disorder of bone marrow function. The molecular diagnosis can be established in a female proband by identification of a heterozygous pathogenic variant in one of the 22 genes associated with DBA. The molecular diagnosis can be established in a male proband by identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA or identification of a hemizygous pathogenic variant in GATA1 or TSR2 (associated with X-linked inheritance).Treatment of manifestations: Corticosteroid treatment, recommended in children older than age 12 months, improves the red blood cell count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is necessary during the first year of life to avoid steroid-induced toxicity in those not responsive to a trial of corticosteroids at age 12 months and in individuals who relapse. Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Ocular, skeletal, genitourinary, cardiac, and endocrine complications are best managed in collaboration with appropriate subspecialists. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities. Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions. Corticosteroid-related side effects must also be closely monitored, especially as related to risk for infection, growth deficiency, and loss of bone density in growing children. Often individuals will be placed on transfusion therapy if these side effects are intolerable. Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and (in children) growth. Evaluation by an endocrinologist for those who are steroid dependent and those at risk for transfusion iron overload. Cancer surveillance includes history, physical examination, and blood counts every four to six months. If red blood cell, white blood cell, or platelet counts fall rapidly, bone marrow aspirate with biopsy and cytogenetic studies (including karyotype and FISH analysis) to look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with myelodysplastic syndrome or leukemia. Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which can cause neutropenia); infection (especially in individuals on corticosteroids). Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives of a proband with a known pathogenic variant allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. Pregnancy management: Management by an obstetrician with expertise in high-risk pregnancies and hematologists with experience in bone marrow failure syndromes. During pregnancy the maternal hemoglobin level must be monitored. Use of low-dose aspirin up to 37 weeks' gestation may help prevent vasculo-placental complications in women with a history of a problematic pregnancy.DBA is most often inherited in an autosomal dominant manner; GATA1-related and TSR2-related DBA are inherited in an X-linked manner. Autosomal dominant. Approximately 40%-45% of individuals with autosomal dominant DBA have inherited the pathogenic variant from a parent; approximately 55%-60% have a de novo pathogenic variant. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the pathogenic variant. X-linked. Males with GATA1- or TSR2-related DBA pass the pathogenic variant to all of their daughters and none of their sons. Women heterozygous for a GATA1 or TSR2 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the GATA1 or TSR2 pathogenic variant has been identified in the family. Once the DBA-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. 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Undescended testis (UDT) is a common abnormality, affecting about 1/20 males at birth. Half of these have delayed testicular descent, with the testis in the scrotum by 10-12 weeks after term. Beyond this spontaneous descent is rare. Current treatment recommendations are that UDT beyond 3 months of age need surgery before 12 months of age. Some children have scrotal testes in infancy but develop UDT later in childhood because the spermatic cord does not elongate with age, leaving the testes behind as the scrotum moves further from the groin with growth of the pelvis. This is now known as ascending/acquired cryptorchidism, and orchidopexy is controversial. Many authors recommend surgery once the testes no longer reside spontaneously in the scrotum, but some groups recommend conservative treatment. The fetal testis descends in 2 separate hormonal and anatomical steps, with the first step occurring between 8-15 weeks’ gestation. Insulin-like hormone 3 (INSL3) from developing Leydig cells stimulates the genito-inquinal ligament, or gubernaculum, to swell where it ends in the inguinal area of the abdominal wall. This holds the testis near the future inguinal canal as the fetal abdomen enlarges. By contrast, in female fetuses, lack of INSL3 allows the gubernaculum to elongate into a round ligament and lets the ovary move away from the groin. The second or inguinoscrotal phase is controlled by androgen and occurs between 25-35 weeks’ gestation, where the gubernaculum and testis migrate together to the scrotum. Androgens guide this complex process, both directly and indirectly via a neurotransmitter, calcitonin gene-related peptide (CGRP), released from the genitofemoral nerve. After migration is complete the proximal processus vaginalis closes (preventing inguinal hernia) and then the fibrous remnant disappears completely, allowing the spermatic cord to elongate with age, to keep the testis scrotal. The transabdominal phase is a simple mechanical process, and abnormalities are uncommon, with intra-abdominal testes found in 5-10% of boys with UDT. Anomalies of the complex inguinoscrotal phase account for most UDT seen clinically. The undescended testis suffers heat stress when not at the lower scrotal temperature (33 degrees Celsius), interfering with testicular physiology and development of germ cells into spermatogonia. UDT interrupts transformation of neonatal gonocytes into type-A spermatogonia, the putative spermatogenic stem cells at 3-9 months of age. Recent evidence suggests orchidopexy between 6-12 months improves germ cell development, with early reports of improved fertility, but little evidence yet for changes in malignancy prognosis. Hypospadias is also a common abnormality in newborn males, affecting about 1/150 boys. Androgens control masculinization of the genital tubercle into penis between 8-12 weeks’ gestation, with tubularization of the urethra from the perineum to the tip of the glans. If this process is disrupted hypospadias occurs, with a variable proximal urethral meatus, failed ventral preputial development producing a dorsal hood, and discrepancy in the ventral versus dorsal penile length, causing a ventral bend in the penis, known as chordee. Surgery to correct hypospadias is recommended between 6-18 months, as technical advances now allow operation to be done before the infant acquires long-term memory of the surgery. Severe hypospadias overlaps with disorders of sex development (DSD), so that babies without a fused scrotum containing 2 testes and who present with ‘hypospadias’ need full DSD investigations at birth. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.Copyright © 2000-2025, MDText.com, Inc.