MedGen

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway. Clinical manifestations and age of onset vary among individuals even in the same family. Neonatal onset (~8% of affected individuals). Manifestations of hyperammonemia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Infantile, childhood, and adult onset (~92%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia. [from GeneReviews]

PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characterized by renal hypodysplasia and abnormalities of the optic nerve; with improved access to molecular testing, a wider range of phenotypes has been recognized in association with pathogenic variants in PAX2. Abnormal renal structure or function is noted in 92% of affected individuals and ophthalmologic abnormalities in 77% of affected individuals. Renal abnormalities can be clinically silent in rare individuals. In most individuals, clinically significant renal insufficiency / renal failure is reported. End-stage renal disease requiring renal transplant is not uncommon. Uric acid nephrolithiasis has been reported. Ophthalmologic abnormalities are typically described as optic nerve coloboma or dysplasia. Iris colobomas have not been reported in any individual with PAX2–related disorder. Ophthalmologic abnormalities may significantly impair vision in some individuals, while others have subtle changes only noted after detailed ophthalmologic examination. Additional clinical findings include high-frequency sensorineural hearing loss, soft skin, and ligamentous laxity. PAX2 pathogenic variants have been identified in multiple sporadic and familial cases of nonsyndromic renal disease including renal hypodysplasia and focal segmental glomerulosclerosis. [from GeneReviews]

Developmental and epileptic encephalopathy-92 (DEE92) is characterized in most patients by onset of seizures in infancy or childhood and associated with global developmental delay and variable impairment of intellectual development. The seizure type and severity varies, and seizures may be intractable in some patients. Some patients are severely affected, unable to walk or speak, whereas others show some development. Additional neurologic features, including cortical blindness, dystonia, and spasticity, may occur. Mutations occur de novo (summary by Hamdan et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Spermatogenic failure-92 (SPGF92) is characterized by male infertility due to asthenozoospermia. Despite markedly reduced progressive motility, sperm morphology may appear normal on light microscopy, or show short or irregular-caliber flagella. Ultrastructural analysis of axonemal cross-sections reveals defects of the radial spokes and doublet microtubules (Li et al., 2023; Hwang et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). [from OMIM]

Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets. Hematopoietic stem cell transplantation may be curative (summary by Beaussant-Cohen et al., 2019 and Levy et al., 2021). [from OMIM]

Retinitis pigmentosa-92 (RP92) is characterized by relatively mild disease, with onset of night blindness and vision loss in the third to sixth decades of life. Patients show abnormal pigmentation of the retina and have reduced scotopic responses on electroretinography (Zhang et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of RP, see 268000. [from OMIM]

Autosomal recessive spastic paraplegia-92 (SPG92) is a slowly progressive neurodegenerative disorder with onset of lower limb spasticity and gait abnormalities in the first (more common) or second decade of life. More variable features include upper limb involvement, tremor, urinary urgency, muscle weakness and atrophy, and mild peripheral neuropathy. Mild cognitive deficits have been reported in some patients (Rebelo et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800. [from OMIM]

Tetraploidy is an extremely rare chromosomal anomaly, polyploidy, when an affected individual has four copies of each chromosome, instead of two, resulting in total of 92 chromosomes in each cell. The phenotype is severe with multiple congenital anomalies, including central nervous system, ocular, cardiac, renal, and/or genital malformations and limb defects. Most patients show severe intrauterine growth retardation, hypotonia, failure to thrive and developmental delay. It is usually associated with miscarriage. [from ORDO]