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. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. 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 pulmonary insufficiency and hypercalcemia. 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 alkaline phosphatase activity. Severe childhood (juvenile): variable presenting features progressing to rickets. Mild childhood: low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots. Adult: characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Odontohypophosphatasia: characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations.

N-acetylglutamate synthase deficiency 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).

Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise three overlapping phenotypes that are usually simplex (i.e., a single occurrence in a family), but rarely may be observed in different members of the same family or may evolve from one clinical syndrome to another in a given individual over time. The three classic phenotypes caused by mtDNA deletions are Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). KSS is a progressive multisystem disorder defined by onset before age 20 years, pigmentary retinopathy, and PEO; additional features include cerebellar ataxia, impaired intellect (intellectual disability, dementia, or both), sensorineural hearing loss, ptosis, oropharyngeal and esophageal dysfunction, exercise intolerance, muscle weakness, cardiac conduction block, and endocrinopathy. Pearson syndrome is characterized by sideroblastic anemia and exocrine pancreas dysfunction and may be fatal in infancy without appropriate hematologic management. PEO is characterized by ptosis, impaired eye movements due to paralysis of the extraocular muscles (ophthalmoplegia), oropharyngeal weakness, and variably severe proximal limb weakness with exercise intolerance. Rarely, a mtDNA deletion can manifest as Leigh syndrome.

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 failure to thrive, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-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 dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired renal function. Additional manifestations include bone demineralization (rickets, osteomalacia), growth deficiency, sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-dRTA), and hereditary hemolytic anemia (in some individuals with SLC4A1-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).