A condition characterized by recurrent, self-limiting episodes of vomiting associated with intense nausea, pallor, and lethargy. It is commonly a migraine precursor.

Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase (ALP). Biallelic ALPL pathogenic variants often result in severe hypophosphatasia that can result in stillbirth without mineralized bone, while heterozygous ALPL pathogenic variants are more likely to manifest as modest, mild, or even asymptomatic disease. Regardless of the number of ALPL pathogenic variants, many individuals with hypophosphatasia suffer from pain, disability, and reduced quality of life. Variability of clinical manifestations is common in both childhood and adult forms of hypophosphatasia and even occurs within affected families. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features. Perinatal (severe): Characterized by restrictive lung disease, respiratory failure, vitamin B6-dependent seizures, hypercalcemia with high morbidity, and mortality Perinatal (benign): Prenatal skeletal manifestations that slowly resolve into one of the milder forms Infantile: Onset between birth and age six months of clinical features of rickets without elevated serum ALP activity Severe childhood (juvenile): Variable presenting features progressing to rickets Mild childhood: Present later in childhood without rachitic disease, low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots Adult: Characterized by osteomalacia and stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Adults with hypophosphatasia may also have significant bone pain and pronounced non-skeletal disease, with muscle weakness, dental problems, and reduced quality of life. Odontohypophosphatasia: Characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations

N-acetylglutamate synthase deficiency (NAGSD) is an autosomal recessive disorder of the urea cycle. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (237300), since the CPS1 enzyme (608307) has an absolute requirement for NAGS (Caldovic et al., 2007).

Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms.

Cronkhite-Canada syndrome is characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, skin hyperpigmentation, and diarrhea. It is associated with high morbidity (summary by Sweetser et al., 2012).

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.

Any sarcoidosis in which the cause of the disease is a mutation in the HLA-DRB1 gene.

Immunodeficiency-27A (IMD27A) results from autosomal recessive (AR) IFNGR1 deficiency. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. The disorder can thus be categorized as a form of mendelian susceptibility to mycobacterial disease (MSMD). Bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Plasma from patients with complete AR IFNGR1 deficiency usually contains large amounts of IFNG (147570), and their cells do not respond to IFNG in vitro. In contrast, cells from patients with partial AR IFNGR1 deficiency, which is caused by a specific mutation in IFNGR1, retain residual responses to high IFNG concentrations. Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008).

Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-related dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of hereditary dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired kidney function. Additional manifestations include bone demineralization (rickets, osteomalacia), sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-related dRTA), hereditary hemolytic anemia (in some individuals with SLC4A1-related dRTA), and amelogenesis imperfecta (in WDR72-related dRTA).

Immunodeficiency-82 with systemic inflammation (IMD82) is a complex autosomal dominant immunologic disorder characterized by recurrent infections with various organisms, as well as noninfectious inflammation manifest as lymphocytic organ infiltration with gastritis, colitis, and lung, liver, CNS, or skin disease. One of the more common features is inflammation of the stomach and bowel. Most patients develop symptoms in infancy or early childhood; the severity is variable. There may be accompanying fever, elevated white blood cell count, decreased B cells, hypogammaglobulinemia, increased C-reactive protein (CRP; 123260), and a generalized hyperinflammatory state. Immunologic workup shows variable B- and T-cell abnormalities such as skewed subgroups. Patients have a propensity for the development of lymphoma, usually in adulthood. At the molecular level, the disorder results from a gain-of-function mutation that leads to constitutive and enhanced activation of the intracellular inflammatory signaling pathway. Treatment with SYK inhibitors rescued human cell abnormalities and resulted in clinical improvement in mice (Wang et al., 2021).

Combined oxidative phosphorylation deficiency-52 (COXPD52) is an autosomal recessive infantile mitochondrial complex II/III deficiency characterized by lactic acidemia, multiorgan system failure, and abnormal mitochondria. Intrafamilial variability has been reported (Farhan et al., 2014; Hershkovitz et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).