MedGen

Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant renal and liver-related morbidity and mortality in children. The majority of individuals with ARPKD present in the neonatal period with enlarged echogenic kidneys. Renal disease is characterized by nephromegaly, hypertension, and varying degrees of renal dysfunction. More than 50% of affected individuals with ARPKD progress to end-stage renal disease (ESRD) within the first decade of life; ESRD may require kidney transplantation. Pulmonary hypoplasia resulting from oligohydramnios occurs in a number of affected infants. Approximately 30% of these infants die in the neonatal period or within the first year of life from respiratory insufficiency or superimposed pulmonary infections. With neonatal respiratory support and renal replacement therapies, the long-term survival of these infants has improved to greater than 80%. As advances in renal replacement therapy and kidney transplantation improve long-term survival, it is likely that clinical hepatobiliary disease will become a major feature of the natural history of ARPKD. In addition, a subset of individuals with this disorder are identified with hepatosplenomegaly; the renal disease is often mild and may be discovered incidentally during imaging studies of the abdomen. Approximately 50% of infants will have clinical evidence of liver involvement at diagnosis although histologic hepatic fibrosis is invariably present at birth. This can lead to progressive portal hypertension with resulting esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Other hepatic findings include nonobstructed dilatation of the intrahepatic bile ducts (Caroli syndrome) and dilatation of the common bile duct, which may lead to recurrent or persistent bacterial ascending cholangitis due to dilated bile ducts and stagnant bile flow. An increasing number of affected individuals surviving the neonatal period will eventually require portosystemic shunting or liver transplantation for complications of portal hypertension or cholangitis. The classic neonatal presentation of ARPKD notwithstanding, there is significant variability in age and presenting clinical symptoms related to the relative degree of renal and biliary abnormalities. [from GeneReviews]

Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. Expression of the HBG1 and HBG2 genes, which encode the gamma isoforms of HbF, is normally suppressed shortly before birth and replaced by expression of the beta- (HBB; 141900) or delta- (HBD; 142000) chains, which form adult hemoglobin. Adults normally have less than 1% HbF, whereas heterozygotes for HPFH have 5 to 30% HbF. HPFH heterozygotes have essentially normal red cell indices and a rather homogeneous distribution of HbF among red cells, termed 'pancellular.' Homozygotes for HPFH can express HbF in up to 100% of red blood cells (Thein and Craig, 1998). Delta-beta thalassemia is a hemoglobin disorder characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis from the affected chromosome. Individuals with delta-beta thalassemia have hypochromic, microcytic anemia and increased HbF, which may mitigate the anemia depending on the level of HbF. Delta-beta thalassemia and some forms of HPFH result from deletions within the beta-globin gene cluster on chromosome 11p15; this has been referred to as 'deletional' HPFH. HPFH can also result from point mutations in the promoter regions of the gamma globulin genes HBG1 and HBG2; this has been referred to as 'non-deletional' HPFH (Ottolenghi et al., 1982; Forget, 1998). Forget (1998) noted that HPFH and delta-beta thalassemia are not clearly distinct disorders, but rather show partially overlapping features that may defy classification. Higher expression of HbF is often termed 'pancellular,' whereas lower expression of HbF is often termed 'heterocellular,' although these represent a spectrum. Approximately 10% of the population has HPFH manifest as modest elevations of HbF (1 to 4%) present in a subset of red cells (about 4.5%) termed F cells. This is also sometimes referred to as 'heterocellular' HPFH, and is considered to be a multifactorial trait influenced by multiple genetic loci (Thein and Craig, 1998). [from OMIM]

Individuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete. A little over half of individuals diagnosed with this recurrent deletion have intellectual disability or developmental delay, mainly in the areas of speech acquisition and cognitive function. In the majority of individuals, cognitive impairment is mild. Other features reported in diagnosed individuals include epilepsy (in ~30%), mild hypotonia, and neuropsychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorder, schizophrenia, and aggressive or self-injurious behavior). Congenital malformations are uncommon. [from GeneReviews]

Atopic dermatitis (also known as atopic eczema) is a disorder characterized by inflammation of the skin (dermatitis). The condition usually begins in early infancy, and it often disappears before adolescence. However, in some affected individuals the condition continues into adulthood; in others, it does not begin until adulthood. Hallmarks of atopic dermatitis include dry, itchy skin and red rashes that come and go. The rashes can occur on any part of the body, although the pattern tends to be different at different ages. In affected infants, the rashes commonly occur on the face, scalp, hands, and feet. In children, the rashes are usually found in the bend of the elbows and knees and on the front of the neck. In adolescents and adults, the rashes typically occur on the wrists, ankles, and eyelids in addition to the bend of the elbows and knees. Scratching the itchy skin can lead to oozing and crusting of the rashes and thickening and hardening (lichenification) of the skin. The itchiness can be so severe as to disturb sleep and impair a person's quality of life.

The word "atopic" indicates an association with allergies. While atopic dermatitis is not always due to an allergic reaction, it is commonly associated with other allergic disorders: up to 60 percent of people with atopic dermatitis develop asthma or hay fever (allergic rhinitis) later in life, and up to 30 percent have food allergies. Atopic dermatitis is often the beginning of a series of allergic disorders, referred to as the "atopic march." Development of these disorders typically follows a pattern, beginning with atopic dermatitis, followed by food allergies, then hay fever, and finally asthma. However, not all individuals with atopic dermatitis will progress through the atopic march, and not all individuals with one allergic disease will develop others.

Individuals with atopic dermatitis have an increased risk of developing other conditions related to inflammation, such as inflammatory bowel disease, rheumatoid arthritis, and hair loss caused by a malfunctioning immune reaction (alopecia areata). They also have an increased risk of having a behavioral or psychiatric disorder, such as attention-deficit/hyperactivity disorder (ADHD) or depression.

In a particular subset of individuals with atopic dermatitis, the immune system is unable to protect the body from foreign invaders such as bacteria and fungi (which is known as immunodeficiency). These individuals are prone to recurrent infections. Most also have other allergic disorders, such as asthma, hay fever, and food allergies.

Atopic dermatitis can also be a feature of separate disorders that have a number of signs and symptoms, which can include skin abnormalities and immunodeficiency. Some such disorders are Netherton syndrome; immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome; and severe dermatitis, multiple allergies, metabolic wasting (SAM) syndrome. [from MedlinePlus Genetics]

Herpes simplex virus (HSV)-1 is most often associated with infection of the oral mucosa. Primary infection is most commonly asymptomatic, but it may lead to symptoms usually involving the mucosa and skin. Following replication at the infection site, HSV-1 enters the epithelial endings of sensory neurons and travels up the trigeminal cranial nerves to the trigeminal ganglia, where latent infection is established. Reactivation of HSV-1, usually in the form of herpes labialis (cold sores), may occur in 20 to 40% of the population. HSV-1 seroprevalence is high, with over 85% of adults between the ages of 20 and 40 years infected. HSV-1 rarely infects the central nervous system (CNS), resulting in herpes simplex encephalitis (HSE), with an incidence of 2 to 4 per 1,000,000 people per year. In HSE, HSV-1 invades and replicates in neurons and glial cells, where focal necrotizing infections occur, primarily affecting the temporal and subfrontal regions of the brain. Untreated, HSE is fatal in at least 70% of cases, although the mortality and morbidity have been drastically reduced with antiviral therapy. Approximately one-third of all HSE cases are due to primary infections, and 30% of all HSE cases occur in children under the age of 20 years. Among children, HSE peaks between 3 months and 3 years of age, coinciding with the time of primary infection. In a subset of children, HSE results from a series of monogenic primary immunodeficiencies that impair UNC93B1- and TLR3 (603029)-dependent production of IFNA (147660)/IFNB (147640) and IFNG (147570) in the CNS (summary by Sancho-Shimizu et al., 2007). Genetic Heterogeneity of Susceptibility to Acute Infection-Induced Encephalopathy, including Herpes Simplex Encephalitis (HSE) For other forms of susceptibility to acute infection-induced encephalopathy, see herpes-specific IIAE2 (613002), caused by mutation in the TLR3 gene (603029) on chromosome 4q35; IIAE3 (608033), caused by mutation in the RANBP2 gene (601181) on chromosome 2q12; IIAE4 (614212), caused by mutation in the CPT2 gene (600650) on chromosome 1p32; herpes-specific IIAE5 (614849), caused by mutation in the TRAF3 gene (601896) on chromosome 14q32; herpes-specific IIAE6 (614850), caused by mutation in the TICAM1 gene (607601) on chromosome 19p13; herpes-specific IIAE7 (616532), caused by mutation in the IRF3 gene (603734) on chromosome 19q13; herpes-specific IIAE8 (617900), caused by mutation in the TBK1 gene (604834) on chromosome 12q14; IIAE9 (618426), caused by mutation in the NUP214 gene (114350) on chromosome 9q34; herpes-specific IIAE10 (619396), caused by mutation in the SNORA31 (619378) on chromosome 13q14; IIAE11 (619441), caused by mutation in the DBR1 gene (607024) on chromosome 3q22; and IIAE12 (620461), caused by mutation in the RNH1 gene (173320) on chromosome 11p15. [from OMIM]

Dystonia-30 (DYT30) is an autosomal dominant neurologic disorder characterized by the onset of symptoms in the first decades of life. Patients present with oromandibular, cervical, bulbar, or upper limb dystonia, and usually show slow progression to generalized dystonia. Some patients may lose ambulation. A subset of patients may also have neurocognitive impairment, including mild intellectual disability or psychiatric manifestations (summary by Steel et al., 2020). In a review of the pathogenesis of disorders with prominent dystonia, Monfrini et al. (2021) classified DYT30 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS16. [from OMIM]