Adult Refsum disease …

Neurogenetic Disorders

Updated 09.27.2025
Released 01.02.1996
Expires For CME 09.27.2028

Adult Refsum disease

Authors: Susan Kuranoff BA, Kristie DeMarco BS, Joseph Hacia PhD

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Editor: Andrea Gropman MD

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Adult Refsum disease

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Introduction

Overview

Adult Refsum disease is a rare autosomal recessive disorder that typically presents in young adulthood with a variable combination of early-onset retinitis pigmentosa, anosmia, peripheral polyneuropathy, cerebellar ataxia, sensorineural hearing loss, and ichthyosis and is also often accompanied by shortened metacarpals and metatarsals at birth. It is caused by impaired catabolism of phytanic acid, a dietary branched-chain fatty acid, which leads to its toxic overaccumulation in the body. Although its neurologic manifestations are often irreversible by the time of diagnosis, appropriate dietary interventions can yield meaningful neurologic improvements in some affected individuals.

Key points

	• Adult Refsum disease is an ultra-rare, autosomal recessive disorder caused by an impaired ability to catabolize the branched chain fatty acid phytanic acid that can accumulate to toxic levels in tissues.
	• Adult Refsum disease typically presents in early adulthood with variable combinations of retinitis pigmentosa, anosmia, peripheral polyneuropathy, cerebellar ataxia, sensorineural hearing loss, and ichthyosis and is often associated with shortened metacarpals and metatarsals at birth.
	• Most affected individuals have biallelic loss-of-function variants in the PHYH gene encoding phytanoyl-CoA alpha-hydroxylase, an enzyme involved in phytanic acid catabolism.
	• In humans, phytanic acid is acquired exclusively from dietary sources, primarily ruminant meats and fats, dairy products, and certain fish.
	• Adult Refsum disease is managed through life-long dietary restriction of phytanic acid accompanied by lipid apheresis when the rapid reduction of phytanic acid levels is required.

Historical note and terminology

Adult Refsum disease is a multisystem neurologic syndrome first described by Sigvald Refsum in 1945 and 1946 (98; 99; 19). The original reported cases had what is now recognized as a diagnostic tetrad of clinical findings: retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and high cerebrospinal fluid protein concentration without pleocytosis (99). Postmortem studies of liver and kidney tissue from a person diagnosed with adult Refsum disease revealed fatty infiltrates composed primarily of neutral lipids, providing the first evidence that adult Refsum disease is a lipidosis (61). Over 50% of the total fatty acids isolated from hepatic lipids were a single, unusual species subsequently identified as phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) (61). Adult Refsum disease results from a deficiency in the phytanic acid catabolism, which results in its toxic overaccumulation in tissues (129). In most cases this is caused by an inherited deficiency in the activity of the phytanoyl-coenzyme A hydroxylase, a peroxisomal enzyme required for phytanic acid catabolism via alpha-oxidation (56), encoded by the PHYH gene (55; 83).

Adult Refsum disease, frequently referred to as “Refsum disease,” should not be confused with “infantile Refsum disease,” now classified within the Zellweger spectrum disorder. Zellweger spectrum disorder is the modern term encompassing a group of peroxisome biogenesis disorders (Zellweger syndrome [severe], neonatal adrenoleukodystrophy [moderate], and infantile Refsum disease [milder]) caused by inherited biallelic loss-of-function variants in any of 13 PEX genes (PEX1, 2, 3, 5, 6, 10, 11B, 12, 13, 14, 16, 19, and 26), excluding PEX7 (08). These PEX genes are required for the assembly, structure, and replication of peroxisomes, metabolic membrane-bound organelles central to cellular homeostasis and cell signaling (125). Adult Refsum disease and Zellweger spectrum disorder differ in etiology, clinical presentations, and biochemical profiles, highlighting the need for distinct clinical approaches and management.

Clinical manifestations

Presentation and course

Left untreated, adult Refsum disease is a progressive, degenerative condition that typically presents in early adulthood with a subset (but rarely all) of the following clinical features: retinitis pigmentosa, anosmia/microsmia, sensorimotor neuropathy, hearing loss, cerebellar ataxia, and ichthyosis (Table 1). Cardiac arrhythmias and cardiomyopathy are occasionally observed in adults, whereas shortened metacarpals and metatarsals are often identifiable at birth (Table 1). Elevated plasma phytanic acid levels are required for diagnosis. Carriers of deleterious PHYH or PEX7 gene variants do not manifest clinical signs or symptoms of disease and generally have normal plasma phytanic acid levels.

Table 1. Clinical and Laboratory Features of Adult Refsum Disease

Clinical findings
	• Retinitis pigmentosa+
	• Cataracts++
	• Nystagmus+++
	• Miosis+++
	• Abnormal pupillary reflex+++
	• Macular edema+++
	• Neurogenic hearing loss++
	• Anosmia/Microsmia+++
	• Cerebellar ataxia+
	• Peripheral polyneuropathy (motor and sensory)+
	• Skeletal malformations (short metacarpals and metatarsals)++
	• Cardiac involvement (nonspecific electrocardiogram abnormalities)++
	• Skin changes (dry skin, ichthyosis)+++
Laboratory findings
	• Elevated plasma phytanic acid concentration+
	• Increased CSF protein without pleocytosis+ (limited data)
Key: +Always present, ++Usually present, +++Sometimes present

Clinical course. Night blindness (nyctalopia) is typically the first symptom noticed by affected individuals. Other early manifestations may include ataxia and additional cerebellar signs, frequently misattributed as “clumsiness,” in the initial stages of the disease. As the disease progresses, affected individuals develop peripheral neuropathy that eventually leads to muscle wasting and distal paralysis. The first appearance of symptoms can range from early childhood to the sixth decade but typically occurs in the second or third decade of life (112). When untreated, the disease is progressive with gradual deterioration. Even with treatment, acute exacerbations of symptoms followed by near-complete remission is not uncommon. These exacerbations are precipitated by physiological stress, including pregnancy or an infection. With proper treatment, people with adult Refsum disease can achieve a near-normal life expectancy.

Primary clinical features. Affected individuals are found to exhibit “salt-and-pepper” retinitis pigmentosa (18). The severity of retinal involvement and the extent of the visual field defect may depend on disease stage. Once present, retinal changes are typically irreversible and unresponsive to dietary treatment (43). A case report described a 51-year-old person with adult Refsum disease who underwent electroretinography (ERG) before and after beginning a phytanic acid-restricted diet (06). Although their post-intervention 30 Hz flicker ERG demonstrated significantly improved waveform amplitudes and implicit times in both eyes, suggesting improved retinal function, there was a lack of improvement in Snellen visual acuity (06).

Adult Refsum disease is associated with a chronic, progressive, mixed motor-sensory peripheral neuropathy if untreated (126). Symptoms are generally first noted in the distal lower extremities and then in the small muscles of the hand, usually with symmetrical distribution. Deep sensation modalities are disturbed, and deep tendon reflexes are diminished. Electrophysiological studies demonstrate slowed motor nerve conduction velocities (68; 74). Although ataxia may be secondary to polyneuropathy, the severity of the symptoms suggests an independent component of true cerebellar ataxia. Despite its inclusion in Refsum’s original diagnostic tetrad, siblings with clinical and biochemical features of adult Refsum disease, but without cerebellar involvement, have been reported (34).

Other clinical findings. In the absence of early interventions, such as a phytanic acid-restricted diet, patients may develop late-onset cardiac disease, including arrhythmias, conduction defects, and hypertrophic or dilated cardiomyopathy, which can progress to heart failure and sudden death if untreated (102; 129; 02). Neurogenic hearing loss, anosmia, disturbed pupillary reflex, and miosis suggest cranial nerve involvement. Hearing loss, like retinal degeneration, is generally unresponsive to treatment. Over half of patients exhibit skeletal malformations, ranging from nonspecific features (pes cavus, hammer toes) to specific changes (symmetrical hyperplasia or hypoplasia of fingers, toes, metacarpals, and metatarsals) (136). Skin changes are frequent, ranging from xerosis to ichthyosis, with histology showing hyperkeratosis with lipid droplet accumulation in basal keratinocytes (97; 81).

Late-onset adult Refsum disease presenting as a leukoencephalopathy. An unusual case involved a 69-year-old woman homozygous for a PHYH frameshift loss-of-function variant who presented with progressive dementia, gait apraxia, and memory loss associated with diffuse leukoencephalopathy (07). Plasma lipid analysis showed significantly elevated phytanic acid levels confirming a diagnosis of adult Refsum disease. Brain MRI showed leukoencephalopathy involving the periventricular white matter, subcortical area, and brainstem, with relative sparing of juxtacortical U fibers. Nevertheless, she lacked the following classic features of adult Refsum disease: retinitis pigmentosa, polyneuropathy, cerebellar ataxia, anosmia, ichthyosis, highly elevated CSF protein level, cataract, hearing loss, and skeletal abnormalities.

Prognosis and complications

Although this can happen without clear cause, the exacerbation and remission of symptoms has been associated with stress, intercurrent illness, or pregnancy. A paradoxical rise in plasma phytanic acid levels and clinical relapse may also occur in patients on dietary therapy who experience sudden weight loss. In such cases, plasmapheresis can help with low circulating phytanic acid levels. If neurologic deficits remain reversible, aggressive therapy (eg, weekly plasma exchange) may provide some clinical improvement.

Clinical vignette

GK, a fictitious 55-year-old male, developed night blindness in childhood that worsened in his late teens. At the age of 33, he was diagnosed with retinitis pigmentosa and was also noted to have mild hearing loss. GK had congenital shortening of metacarpals and metatarsals and long-standing dry skin. At the age of 40, he underwent a comprehensive medical evaluation. He exhibited impaired walking ability, a slapping gait, inability to stand on his heels, and bilateral calf atrophy with leg weakness. Knee and triceps reflexes were trace, and ankle reflexes were absent. Examination revealed bilateral pes cavus. GK had reduced pinprick response below the elbows and knees, absent vibration sense below the knees, and impaired position sense in the toes. Nerve conduction velocities were slow, and there was reduced sensory potential amplitudes in the right median and ulnar nerves. GK was not ataxic, and Romberg testing was negative.

His visual, auditory, and olfactory senses were then assessed. GK displayed pupillary abnormalities and iris atrophy bilaterally. Fundoscopy revealed bilateral diffuse retinal pigment epithelial degeneration, midperipheral pigment clumps, and arteriolar narrowing. Electroretinograms were nearly extinguished bilaterally, with severe constriction of visual fields. Slit lamp examination showed bilateral subcapsular lens opacities. Pure-tone audiometry revealed bilateral mid- to high-frequency hearing loss. Auditory brainstem responses suggested subtle bilateral auditory nerve involvement. Smell testing indicated moderate microsmia.

Biochemical and genetic testing was performed to establish a molecular diagnosis. Plasma phytanic acid concentration was markedly elevated at 1600 µmol/L (normal < 10 µmol/L). Whole-exome sequencing identified two deleterious loss-of-function PHYH alleles, a missense variant affecting a conserved residue near an Fe(II) binding site and a nonsense variant in exon 2. A molecular diagnosis of adult Refsum disease was made.

After diagnosis, GK was placed on a low-phytanic acid diet. He also received a prolonged course of plasmapheresis, which lowered circulating phytanic acid levels and improved neuropathy over several years. At the age of 52, vision loss had progressed, but hearing remained stable.

Biological basis

Etiology and pathogenesis

	• Adult Refsum disease results from the toxic accumulation of phytanic acid in tissues due to impaired peroxisomal alpha-oxidation.
	• In over 90% of cases, the cause is inherited deficiency of phytanoyl-CoA hydroxylase (PHYH), an enzyme in the peroxisomal alpha-oxidation pathway.
	• In less than 10% of cases, the cause is inherited deficiency of PEX7, a protein required for the import of PHYH into peroxisomes.

Accumulation of phytanic acid in plasma and tissues. In healthy individuals, plasma phytanic acid levels are nearly undetectable, but it can account for up to 30% of the total plasma fatty acids in some people with adult Refsum disease. Hepatic and renal fatty infiltrates in affected individuals consist of neutral lipids enriched with phytanic acid. Plasma levels of phytanic acid reflect both dietary intake of phytanic acid (or its precursor phytol) and mobilization of phytanic acid from tissue stores.

Origin of phytanic acid. The observed structural similarity between phytanic acid and phytol, the side chain of chlorophyll, led to the hypothesis that dietary intake is the primary source of this branched-chain fatty acid (113). Studies in rats and humans have shown that dietary phytol and phytanic acid are efficiently absorbed and that phytol is efficiently converted to phytanic acid in vivo (113). Nevertheless, chlorophyll-bound phytol is poorly absorbed in both rats and humans, suggesting that green vegetables are not a significant source of dietary phytanic acid (20). In contrast, ruminant fats and dairy products are considered major dietary sources of phytanic acid in humans (78; 79). Rumen bacteria efficiently liberate the phytol from chlorophyll; the released phytol is then absorbed or converted to phytanic acid, which is subsequently stored in fats and adipose tissue. Healthy humans adhering to vegan diets exhibit significantly lower red blood cell phytanic acid levels compared to those on Western diets (130; 87).

Phytanic acid degradation pathway. Cultured primary skin fibroblasts obtained from donors with adult Refsum disease show impaired phytanic acid degradation (131). The methyl branch on the 3-carbon prevents catabolism by the classic beta-oxidation pathway. Instead, alpha-oxidation removes one carbon, repositioning the methyl groups to permit subsequent beta-oxidation. Successive rounds of beta-oxidation yield alternating 3- and 2-carbon fragments. Phytanic acid is first converted to alpha-hydroxyphytanic acid and is then decarboxylated, forming pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) and carbon dioxide (112). Pristanic acid undergoes beta-oxidation, first in peroxisomes and then in mitochondria (125). The 3R, 7R, 11R- and 3S, 7R, 11R- stereoisomers of phytanic acid are found in nature and can be converted to the corresponding 2R, 6R, 10R- and 2S, 6R, 10R- stereoisomers of pristanic acid via alpha-oxidation (32). Peroxisomal beta-oxidation of pristanate requires the S-configuration at carbon-2. Alpha-methylacyl-CoA racemase (AMACR), located in peroxisomes and mitochondria, catalyzes the interconversion of 2R and 2S isomers and is required for complete phytanic acid catabolism.

Phytanic acid catabolism to pristanic acid, followed by three cycles of beta-oxidation, occurs in peroxisomes, with end products shuttled to mitochondria for full oxidation to carbon dioxide and water (125). The first step is peroxisomal activation of phytanic acid to phytanoyl-CoA by long- and very long-chain acyl-CoA synthetases (116; 125). Phytanoyl-CoA is converted to alpha-hydroxyphytanoyl-CoA by phytanoyl-CoA hydroxylase (PHYH) (84). PHYH, a peroxisomal enzyme with an N-terminal peroxisome targeting signal 2 (PTS2), requires the PEX7 protein for matrix import (83). Sterol carrier protein-2 (SCP-2) within peroxisomes may enhance PHYH specificity for phytanic acid (89). Decarboxylation of alpha-hydroxyphytanoyl-CoA yields an aldehyde, pristanal, and formyl-CoA (21; 125). This reaction is catalyzed by 2-hydroxyacyl-CoA lyase 1 (HACL1) with thiamine pyrophosphate (TPP) as cofactor (37; 82). Formyl-CoA spontaneously breaks down to formate and CoA under physiological conditions (21). Formate is translocated to mitochondria and converted to carbon dioxide. Pristanal is oxidized to pristanic acid, reactivated to its CoA thioester, and degraded by peroxisomal beta-oxidation, with end products converted to carbon dioxide and water in mitochondria (116; 125).

Peroxisomal phytanic acid alpha-oxidation is regulated by additional mechanisms. For example, it could be controlled by levels of free fatty acids versus CoA-thioesters (ie, phytanoyl-CoA, pristanoyl-CoA). Peroxisomes contain acyl-CoA thioesterase (ACOT6), an acyl-CoA thioesterase specific for these branched-chain fatty acids (132). Fatty acid-binding protein 1 (FABP1 or L-FABP) plays a key role in phytanic acid metabolism (03; 04). Fabp1 (L-FABP) overexpression in mice enhanced cellular phytanic acid uptake and alpha-oxidation, with minimal effect on esterification. Conversely, murine cells in which the Fabp1 gene was disrupted showed reduced phytanic acid uptake and alpha-oxidation rates. This suggests that other tissue-specific FABP isoforms may influence phytanic acid metabolism in tissues affected by adult Refsum disease (eg, nervous system and heart).

Omega oxidation provides an alternative, minor pathway for phytanic acid degradation (127). Here, the terminal (omega) methyl group is oxidized to a carboxylic acid, yielding a dicarboxylic acid that can be partially degraded from the omega end by beta-oxidation. People on Western diets typically consume 50 to 100 mg phytanic acid daily (41; 134). In adult Refsum disease, omega oxidation capacity was found to be about 7 mg/day (134). Omega oxidation reactions are NADPH-dependent and involve specific cytochrome P450 enzymes (127). Because phytanic acid is a substrate for human UDP-glucuronosyltransferases, it was suggested that some elimination may occur via glucuronidation (73).

Enzyme defect in adult Refsum disease. Evidence supporting the hypothesis that adult Refsum disease is caused by a PHYH deficiency was obtained when a liver biopsy from an affected individual showed no detectable PHYH activity relative to controls (56). The PHYH gene was independently cloned by two groups (55; 83). PHYH loss-of-function variants have been identified in people with adult Refsum disease (55; 53; 54; 83; 15). About 67% were missense variants; the remainder included insertions, deletions, and splice-site variants. Structure-function analyses showed most clinical PHYH deleterious variants impaired phytanoyl-CoA hydroxylation, though one such variant did not (88). A PHYH missense variant (P29S) was fully active, but its location near the N-terminus suggests impaired targeting or processing (ie, removal of N-terminal PTS2 by the peroxisomal TYSND1 protease) as the disease mechanism (85). Human PHYH crystal structure data show many disease-causing variants cluster near the Fe++ or 2-oxoglutarate binding pockets (80).

Following up on linkage studies (135), biochemical and variant analyses identified PEX7 as a second adult Refsum disease locus (123). A person diagnosed with adult Refsum disease due to PEX7 deficiency (one null, one hypomorphic allele) exhibited clinical phenotypes indistinguishable from those caused by a PHYH deficiency (47). PEX7 deficiency, especially more severe, primarily causes rhizomelic chondrodysplasia punctata type 1 (RCDP1), a congenital disorder more severe than adult Refsum disease (09). PEX7 is a cytoplasmic receptor for proteins with PTS2-containing proteins, including phytanoyl-CoA hydroxylase (PHYH), alkyl-dihydroxyacetone phosphate synthase (AGPS or ADHAPS), and peroxisomal 3-oxoacyl-CoA thiolase 1 (ACAA1) (69). When PEX7 protein activity is deficient, import of PTS2-containing proteins into the peroxisome matrix is impaired, resulting in biochemical abnormalities. A case report involving affected twins supports a broad phenotypic spectrum for PEX7 deficiency and indicates additional peroxisomal biochemical testing may be warranted for a newly identified patient (77). Although adult Refsum disease is easily distinguished from severe RCDP1, milder RCDP1 phenotypes can overlap with adult Refsum disease (129).

Pathogenesis. Experimental evidence suggests that elevated plasma and tissue levels of phytanic acid directly or indirectly drive disease manifestations. Reducing phytanic acid body burden through dietary therapy can improve clinical outcomes. Several pathomechanisms have been proposed (52).

Activated phytanoyl-CoA can serve as the substrate for incorporation into phospholipids, triacylglycerols, and other lipids. In cultured retinal cells, exogeneous phytanic acid is incorporated into phospholipids, increasing membrane fluidity without enhancing susceptibility to lipid peroxidation (138). Phytanic acid did not competitively inhibit alpha-tocopherol uptake, weakening the hypothesis that membrane phytanic acid disrupts vitamin E function (138). In cultured normal human prostate epithelial and PC-3 carcinoma cells, treatment with phytanic acid plus all-trans retinol (vitamin A) produced retinyl phytanate, a retinyl ester, though its relevance to adult Refsum disease is unclear (121). Mice deficient in sterol carrier protein-x (encoding Scp2, a putative phytanic acid–binding protein, and Scpx, a thiolase for peroxisomal beta-oxidation of pristanic acid) fed a phytol-enriched diet accumulated phytanic acid in myocardial membrane phospholipids (86). This was associated with bradycardia, conduction defects, and sudden death, strengthening the hypothesis that arrhythmias may contribute to mortality in untreated adult Refsum disease. Because PHYH can hydroxylate a variety of 3-methyl-branched fatty acyl-CoAs (36), accumulation of other 3-methyl fatty acids could also contribute to pathogenesis.

Elevated phytanic acid levels may alter the behavior of plasma membrane ion transporters. It was first reported that rising plasma phytanic acid levels reduced the maximal velocity of the erythrocyte sodium–lithium countertransporter (133). In purified synaptic vesicles from young rat brain cortex, membrane synaptic Na/K ATPase activity was decreased when phytanic acid or pristanic acid were present in assays (13; 14). Busanello and colleagues concluded that phytanic and pristanic acids may impair synaptic neurotransmission.

Multiple lines of evidence suggest that elevated phytanic acid levels can disrupt mitochondrial functions. In isolated rat brain mitochondria, phytanic acid triggered cytochrome c release, suggesting activation of the mitochondrial apoptotic pathway (101; 109). Phytanic and pristanic acid induced nitric oxide–dependent apoptosis, possibly via autocrine TNF-alpha secretion in cultured vascular smooth muscle cells (51). In rat brain synaptosomes, free phytanic acid uncoupled mitochondria, inhibited electron transport, and blocked adenine nucleotide exchange, disrupting ATP supply (108). In rat hippocampal astrocytes, phytanic acid activated intracellular calcium stores, producing mitochondrial depolarization and generating reactive oxygen species, potentially relevant to neurologic features of adult Refsum disease (58). Similarly, in rat heart mitochondria, phytanic acid disrupted mitochondrial bioenergetics and calcium homeostasis, possibly underlying cardiomyopathy in some patients (139). In isolated rat heart and liver mitochondria, phytanic acid increased reactive oxygen species generation by partially inhibiting electron transport and, most likely, by altering membrane fluidity (110). Phytanic acid also decreased ATP synthesis and mitochondrial membrane potential in human fibroblasts (65). In young rat brain cortex homogenates, increasing phytanic or pristanic acid concentrations decreased respiratory-chain activity at specific complexes (13; 14). Subsequent work showed both phytanic and pristanic acids uncouple oxidative phosphorylation (11; 12).

Other studies have examined how phytanic acid promotes oxidative stress across diverse model systems. In mixed cultures of rat hippocampal neurons, astrocytes, and oligodendrocytes, phytanic or pristanic acid increased reactive oxygen species production and markedly elevated intracellular calcium by the inositol triphosphate signaling cascade (104). Subsequent studies revealed the involvement of a G-protein coupled receptor, GPR40, in this process (67). In rat cerebellar and cortical homogenates, phytanic acid exposure elevated lipid peroxidation and protein oxidative damage, though evidence suggested it was not a direct oxidant (72). Similar effects were observed in heart mitochondria, and it was proposed that phytanic acid–induced disturbances of cellular energy and redox homeostasis may contribute to cardiomyopathy in adult Refsum disease (42). In rat aortic smooth muscle cells, there was evidence that phytanic acid transactivates epidermal growth factor receptor (EGFR) and induces NADPH oxidase (NOX) activity (25). The authors suggest that nitric oxide may not be the only reactive nitrogen species or reactive oxygen species generated due to phytanic acid exposure.

Although phytanic acid is a physiological ligand for the ligand-activated nuclear hormone receptor PPAR-alpha (28; 137; 142), the role of phytanic acid–related transcriptomic changes in adult Refsum disease pathogenesis is unclear. PHYH is upregulated in cells incubated with phytanic acid (142; 141). Physiological phytanic acid levels enhanced 2-deoxy-D-glucose uptake in rat hepatocytes by upregulating mRNA for glucose transporter-1 and -2 and glucokinase (46). Phytanic acid combined with retinoic acid receptor ligands induced intestinal retinoic acid hydroxylase and retinoic acid metabolism (70). Phytanic acid induced differentiation of both white and brown adipose and induced uncoupling protein-1 (UCP1) mRNA expression in brown adipose tissue (106; 105; 107). UCP1 expression was enhanced by co-transfection of brown adipocytes with a retinoid X receptor expression vector, which supports another report that phytanic acid is a natural ligand for retinoid X receptor beta (94). Later studies showed that phytanoyl-CoA and pristanoyl-CoA exhibit high affinity for PPAR-alpha, whereas the respective free fatty acids showed only weak binding (49).

PHYH has been reported to interact with several different binding partners. It binds the immunophilin FKBP52, suggesting a role in cellular signaling (16). A brain-specific protein, PHYH-AP1 (now BAP4), binds to PHYH in a yeast 2-hybrid system (71) and also interacts with brain-specific angiogenesis inhibitor 1 (BAI1) (63). It was postulated that PHYH interacts with BAI1 through BAP4, potentially contributing to central neurologic symptoms of disease. In a transgenic mouse model, selective overexpression of PHYH-AP1 in the heart (atrium) caused tachycardia and arrhythmia susceptibility, possibly relevant to adult Refsum disease (62). In rats, visual stimulation is essential for maintaining PAHX-AP1 mRNA expressions in the retina and visual cortex, which may suggest involvement in retinal function (01). Two hybrid studies have identified that murine long-chain fatty acyl-CoA synthetase (mLACS) expressed in the brain interacts with murine Phyh (59), and human PHYH interacts with human coagulation factor VIII (17). They collectively implicated PHYH as having a role in nervous system and coagulation functions.

Phytanic acid may also modulate other physiological processes. In mouse neuroblast Neuro2a cells, phytanic acid exacerbated mitochondrial dysfunction, activated histone deacetylase activity, reduced histone acetylation, and promoted cell death (90). Multiomic analyses of phytol-treated fibroblasts from healthy donors and those with adult Refsum disease identified 53 metabolites, several linked to amino acid metabolism, predicted to distinguish between the two groups (131). Phytanic acid has also been reported to exert immunomodulatory effects. The stereoisomer 3RS,7R,11R-phytanic acid (3RS-PHY) inhibited production of autoimmune-related T-cell cytokines (eg, IFN-gamma, IL-17A) in murine immune cells. It also suppressed B-cell antibody production and macrophage nitric oxide synthesis (91). In lupus-prone female BWF1 mice, phytanic acid restored splenic macrophage efferocytosis by activating PPAR-gamma and LXR signaling pathways, possibly by upregulating CD36 activity (45).

Mouse model of adult Refsum disease. A mouse model of adult Refsum disease with a biallelic deletion of exons 4 to 7 of the Phyh gene has been reported (33). On a mixed (Swiss/129SVJ/FVB) background, homozygous Phyh-null (knockout) mice showed no overt abnormalities under standard laboratory conditions on chow containing very low levels of phytanic acid and its precursor, phytol. When fed a 0.25% phytol-supplemented diet, Phyh-knockout mice exhibited weight loss due to lipoatrophy with loss of white adipose tissue. Phytanic acid accumulated to high levels in plasma, liver, kidney, testis, and cerebellum. Conversely, plasma levels of other lipids, including cholesterol, triacylglycerol, free fatty acids, and total fatty acids, were decreased in phytol-fed knockout mice. Liver histology revealed steatosis, hepatocyte degeneration, and inflammatory infiltrates with microvesicular steatosis on 0.1% phytol diets and macrovesicular steatosis on 0.25% phytol diets. Testes from Phyh-null mice on either 0.1% or 0.25% phytol diet lacked the full complement of spermatogenic cells. Brains of Phyh-null mice on the 0.25% phytol diet showed prominent reactive astrocytosis and a striking loss of cerebellar Purkinje cells.

Phyh-null mice fed phytol exhibited neuromuscular deficits, including an increased number of paw slips while moving on a grid and absent trunk curl (33). They had an unsteady gait with smaller forepaw and hindpaw print areas and a reduced base of hindpaw support. Peripheral motor nerve conduction velocity was decreased reflecting prolonged action potential latency. However, sciatic nerve histology and myelin basic protein staining revealed no overt demyelination.

Although a 0.1% or 0.25% phytol diet had essentially no effects on wild-type mice (33), others reported that higher phytol levels (0.5% to 1.0%) induced midzonal hepatocellular necrosis and periportal fatty vacuolation (76). High phytanic and pristanic acid levels correlated with increased PPAR-alpha-mediated responses, including weight loss, hepatomegaly, and peroxisome proliferation (76). In sheep, dietary phytol supplementation reduced plasma cholesterol and phospholipid levels during treatment while increasing triglyceride levels (26). Phytol treatment also altered amino acid profiles, elevating serine and glycine while lowering glutamate levels.

Other relevant genetically engineered mouse models of peroxisomal alpha-oxidation deficiency have been reported. For example, an allelic series of Pex7-deficient mice was generated, including homozygous hypomorphic, compound heterozygous (hypomorphic/null), and homozygous null mutants (29). These models showed graded reductions in plasmalogen levels and increases in very long-chain fatty acids and phytanic acid levels in plasma and brain relative to controls (29). Hacl1-knockout mice lack 2-hydroxyacyl CoA lyase (HACL1), a key enzyme for peroxisomal alpha-oxidation (60). When fed a phytol-enriched Western diet (0.2% v/v), these mice showed no overt phenotype but accumulated phytanic and 2-hydroxyphytanic acid in liver, with a marked decrease in heptadecanoic acid levels. Moreover, proteins in the omega-oxidation pathway were upregulated. Overall, Pex7- and Hacl1-deficient mouse models offer valuable experimental platforms for studying physiological responses to phytanic acid overaccumulation.

Genetics. Adult Refsum disease is an autosomal recessive disorder (129). Bilalleic deleterious loss-of-function variants in the PHYH gene (NCBI Refseq NM_006214.4) account for over 90% of known cases. PHYH is located on chromosome 10p13 (chr10:13277799-13300064 in human genome build GRCh38/ng38). Less commonly (< 10% of cases), the disease is caused by deleterious partial loss-of-function variants in the PEX7 gene (NCBI Refseq NM_000288.4). PEX7 is located on chromosome 6q23.3 (chr6:136822592-136913934 in human genome build GRCh38/ng38).

Differential diagnosis

Adult Refsum disease must be distinguished from (i) neurologic syndromes with similar features but normal circulating phytanic acid levels and (ii) other peroxisomal disorders with elevated circulating phytanic acid levels. The clinical and genetic landscapes of hereditary peripheral neuropathies have been reviewed (38). Differential diagnoses include Friedreich ataxia, retinitis pigmentosa, multiple sclerosis, Dejerine-Sottas syndrome, Charcot-Marie-Tooth syndrome, nonspecific heredo-ataxia syndromes, abetalipoproteinemia, Tangier disease, amyotrophic lateral sclerosis, Sjogren-Larsson syndrome, Spielmeyer-Vogt disease, and Tay-Sachs disease. PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), an adult Refsum disease-like disorder caused by ABHD12 deleterious variants, should also be considered (35; 23). Elevated plasma phytanic acid levels rule out all the disorders mentioned and would indicate adult Refsum disease, particularly in adolescents or adults. For example, two sisters initially presenting with an acute demyelinating polyneuropathy suggestive of familial Guillain-Barré syndrome were later diagnosed with adult Refsum disease based on elevated circulating phytanic acid levels (124).

Phytanic acid accumulation is not unique to adult Refsum disease. Impaired ability to degrade phytanic acid leading to elevated plasma levels occurs in peroxisome biogenesis disorders, which include Zellweger spectrum disorder and rhizomelic chondrodysplasia punctata type 1 (RCDP1) (09; 115). Depending on severity, people with Zellweger spectrum disorder may also exhibit elevated plasma concentrations of very long-chain fatty acids (VLCFAs) and pipecolic acid with lowered erythrocyte plasmalogen levels. Cultured primary skin fibroblasts from patients with Zellweger spectrum disorder can also show decreased plasmalogen synthesis. Importantly, signs and symptoms of peroxisome biogenesis disorders are typically present at birth, especially in intermediate and severe cases. Alpha-methylacyl-CoA racemase (AMACR) deficiency can also present as an adult-onset sensory motor neuropathy, but with elevations in both pristanic acid and phytanic acid circulating plasma levels (30). Mildly elevated plasma phytanic acid was also found in one reported case of sterol carrier protein x (SCPx) deficiency (31); this patient presented with leukoencephalopathy, dystonia, and motor neuropathy and had markedly elevated plasma pristanic acid levels. Thus, adult Refsum disease can be diagnosed when patients display the tetrad of clinical features originally described by Refsum, have elevated plasma phytanic acid levels or impaired ability to catabolism, and lack biochemical evidence of more generalized peroxisome dysfunction.

Because PHYH requires thiamine pyrophosphate as a cofactor, it has been suggested that untreated thiamine deficiency (eg, in malnourished individuals) may elevate phytanic acid levels (111). Classical thiamine (vitamin B1) deficiency (beriberi) is associated with polyneuropathy. Wernicke encephalopathy, an acute neuropsychiatric disorder due to thiamine deficiency, is most commonly seen in developed countries in people with chronic heavy alcohol use. Thiamine deficiency also occurs in inborn errors of metabolism, such as thiamine-responsive megaloblastic anemia. Nevertheless, phytanic acid levels have not been extensively studied in people with beriberi, Wernicke encephalopathy, or thiamine-responsive megaloblastic anemia.

Confusing conditions

As discussed in the Historical Note and Terminology section, adult Refsum disease should not be confused with the peroxisome biogenesis disorder, once called “infantile Refsum disease.” Although now an outdated term, it persists in the literature and in clinical practice. The accepted term “Zellweger spectrum disorder” encompasses a group of peroxisome biogenesis disorders (previously classified as Zellweger syndrome [severe], neonatal adrenoleukodystrophy [moderate], and infantile Refsum disease [milder]) caused by biallelic loss-of-function variants in any of 13 PEX genes (PEX1, 2, 3, 5, 6, 10, 11B, 12, 13, 14, 16, 19, and 26), excluding PEX7 (08). Milder Zellweger spectrum disorder (formerly infantile Refsum disease) is a multisystemic disorder that often presents with sensory loss (vision and hearing), neurologic involvement (ataxia, polyneuropathy, leukodystrophy), liver dysfunction, adrenal insufficiency, kidney stones, and ameleogenesis imperfecta of secondary teeth (115). Affected individuals typically display hypotonia and developmental delays (but can have normal intellect), and some develop osteopenia.

Diagnostic workup

Individuals with symptoms of night blindness, gait disturbance, or peripheral neuropathy should be evaluated for adult Refsum disease. A complete neurologic examination is warranted to assess signs of peripheral motor or sensory neuropathy, ataxia, and cranial nerve dysfunction. Ophthalmologic examination should assess for the salt-and-pepper type of retinitis pigmentosa typical of adult Refsum disease as well as visual field defects, miosis, or abnormal pupillary reflexes. Olfactory functional assessment tools, such as the University of Pennsylvania Smell Identification Test, may be informative. In a study of 16 affected individuals, all exhibited complete anosmia or severely impaired smell function despite a median 15 years of dietary treatment (40). Individuals should also be evaluated for ichthyosis. The presence of hand or foot abnormalities in a person with retinitis pigmentosa may be suggestive of adult Refsum disease (57; 120). All symptoms of this disease do not develop simultaneously, and there may be years between the onsets of different symptoms. Thus, diagnosis is often difficult, and early misdiagnosis is not uncommon.

Biochemical and genetic testing is warranted for a clinical diagnostic workup. The primary biochemical test is measurement of the plasma phytanic acid concentration by gas chromatography (GC), GC-mass spectrometry (GC-MS), or liquid chromatography-tandem mass spectrometry (LC-MS/MS) (24). To exclude other peroxisomal diseases, plasma VLCFA and pristanic acid levels, as well as plasmalogen synthesis in cultured fibroblasts, should be evaluated. Genetic testing via whole exon sequencing, whole genome sequencing, or targeted examination of the PHYH and PEX7 genes is valuable, particularly for atypical cases (05). Electrocardiography should be performed to detect the nonspecific changes sometimes seen in affected individuals. Evaluation of CSF protein and cellular content may provide supportive information but are generally unnecessary if plasma phytanic acid level is elevated.

Management

Current standard of care. In humans, phytanic acid is entirely of exogenous origin; thus, restricting dietary intake of this fatty acid and its precursors reduces its accumulation in affected individuals. Both phytanic acid and phytol (a precursor converted to phytanic acid) should be minimized in the diet. Because affected individuals have only a limited residual capacity to degrade phytanic acid, dietary restriction enables the gradual depletion of body stores. Typical Western diets provide 50 to 100 mg/day of phytanic acid, whereas affected individuals can only degrade about 7 to 30 mg/day (41; 134). Thus, intake must be significantly less than 30 mg daily to promote mobilization and elimination of stored phytanic acid.

Major dietary sources include dairy products, ruminant meats and fats, and certain fatty fish, all of which must be dramatically reduced or eliminated from the diet for effective management. Early dietary trials excluded green vegetables because of chlorophyll content, but given the poor bioavailability of chlorophyll-bound phytol, this restriction is likely unnecessary. Although phytanic acid is present in many foods, reliable information on food content is limited. Detailed dietary management strategies and food phytanic acid levels have been reported (75; 78; 79; 50; 10; 103). Although non-leafy vegetables typically have a very low phytanic acid content, some vegetables may harbor phytyl fatty acid esters (trans-phytol esterified with fatty acids) that could contribute to phytanic acid body burden (66).

Evaluating treatment response is challenging because reductions in plasma phytanic acid levels and clinical improvement are typically not rapid. Plasma phytanic acid levels reflect both dietary intake and release from endogenous stores. Large amounts of phytanic acid are stored in adipose triglycerides, possibly slowing mobilization and clearance. In affected individuals on a low phytanic acid diet, sudden weight loss can lead to a rise in plasma concentration and trigger clinical relapses, indicating the important contribution of adipose mobilization. Special protocols should be used to avoid fasting-induced spikes in circulating phytanic acid levels during surgery.

Plasmapheresis has been successfully used in some cases as an adjunct to dietary therapy (75; 50; 44; 39). It can be particularly useful in early disease management or in cases of clinical relapse but is not a practical substitute for lifelong dietary therapy. Therapeutic apheresis with membrane differential filtration has proven safe and effective for long-term disease management (118). Long-term lipid apheresis benefitted four people with severe adult Refsum disease whose symptoms progressed despite adherence to a low phytanic acid diet (140). In another report, lipid apheresis was combined with dietary management in an affected 14-year-old female with night blindness (64). After 30 months, she was maintained solely on a phytanic acid–restricted diet. This suggests that aggressive phytanic acid level reduction may prevent more serious disease sequelae.

Although many symptoms respond to treatment, the progression of retinal changes and hearing loss generally slow or stabilize, with little evidence of significant improvement in most patients (114). Nevertheless, a 51‐year‐old person with adult Refsum disease showed marked improvements in electroretinographic waveform amplitudes and implicit times after initiating a phytanic acid–restricted diet, despite unchanged visual acuity (06).

Several reports indicate that some patients may benefit from cochlear implantation (95; 92; 117; 48). In a newly diagnosed 42-year-old female with classical symptoms, aggressive therapy (dietary phytanic acid restriction and weekly plasma exchange for 9 months) led to nearly normalized cervical and ocular vestibular evoked myogenic potential latencies (122). She also experienced improvements in vestibular neuropathy, peripheral nerve function, and mobility.

Future therapeutic prospects. Perera and colleagues reported two affected brothers (ages 48 and 50 years) treated with the intestinal lipase inhibitor orlistat (93). Despite dietary management and plasmapheresis, their plasma phytanic acid levels remained over 10-fold greater than the upper limit of normal. Both also exhibited progressive neurologic and dermatologic symptoms. They began orlistat therapy (120 mg 3 times a day before meals) in combination with diet and plasmapheresis. After following this regimen for several years, plasma phytanic acid levels fell by more than 50%, and both reported stabilization or improvement of some neurologic symptoms. These findings suggest that further investigation of this approach may be warranted.

Other therapeutic strategies aim to enhance phytanic acid metabolism via small molecules. Kemp and coworkers investigated enhancing the fatty acid omega-oxidation pathway as an alternative means of catabolizing phytanic acid (128). Although no drugs are currently available, they speculated that compounds inducing specific cytochrome P450 isozymes could theoretically increase phytanic acid omega-oxidation. Overall, agents that stimulate the fatty acid omega-oxidation pathway may merit further study in adult Refsum disease.

Outcomes

High levels of phytanic acid have been associated with life-threatening cardiac arrhythmia and peripheral neuropathy, requiring emergency plasmapheresis (75). Without therapy, half of untreated individuals died before the age of 30. Steinberg noted that since dietary therapy was instituted, no deaths have been directly attributable to adult Refsum disease (112). However, later diagnosis can allow large tissue stores of phytanic acid to accumulate in multiple organs, increasing the risk of premature death. Dietary therapy, with or without supplemental plasmapheresis, is effective in decreasing the severity of peripheral nerve dysfunction and ataxia, lowers plasma phytanic acid and CSF protein levels, and improves electrocardiographic findings. Although therapy is thought to offer little or no improvement in existing retinal or hearing deficits, it may slow or prevent further nervous system progression.

Special considerations

Pregnancy

Metabolic stress has long been recognized to exacerbate disease symptoms (112). However, the first detailed report on pregnancy in adult Refsum disease was not reported until 2017 (119). In this report, the mother had an unusually early onset, with symptoms by 3 years of age. She had salt and pepper retinitis pigmentosa, sensorineural hearing loss, ichthyosis, mild developmental delay, and bony abnormalities of the hands and feet. Adult Refsum disease was confirmed at the age of 10 by biochemical and genetic testing. Her plasma phytanic acid level was not well controlled by diet and required occasional plasmapheresis. She became pregnant at the age of 27, with a pre-pregnancy weight of 75.6 kg. In the first trimester, she experienced epigastric and lower abdominal pain, but ultrasound indicated normal fetal development. Following advice from a metabolic physician and a metabolic dietitian, she maintained phytanic acid levels at a higher than desirable, but stable, level. By 5 months, she had gained 7 kg. In the third trimester, she developed sinus tachycardia and shortness of breath. Later pregnancy was marked by breathlessness, fluctuating hypertension, dry skin, and pruritus, all of which improved postpartum. Labor was induced at term, and during labor she received Polycal^® and Calogen^® supplements to reduce the risk of acute metabolic decompensation. She delivered a healthy daughter with a normal phytanic acid level at 6 weeks of age. Postpartum, she developed depression and poor appetite, raising concern because fasting-related lipolysis can elevate plasma phytanic acid levels. Other postpartum issues included episodes of fatigue and general weakness, dyspareunia requiring a refashioning of episiotomy, hypertension, headaches, dizziness, persistent episodes of nausea, vomiting, and epigastric abdominal pain. These gastrointestinal symptoms were eventually attributed to irritable bowel syndrome. The child was reportedly healthy and developing normally.

In 2019, Dubot and colleagues reported on a woman with adult Refsum disease who was homozygous for a PHYH loss-of-function variant and had multiple pregnancies with fetuses homozygous for the same variant (27). She was born into a family with several affected members and diagnosed with adult Refsum disease at 21 years of age. Her initial clinical exam showed bilateral metatarsal shortening but no neurologic signs. The diagnosis was established by biochemical and genetic testing, where she was found homozygous for a deleterious PHYH splice junction variant. Afterwards, she was managed by dietary phytanic acid restriction. She married her first cousin carrying the same deleterious PHYH variant and had seven pregnancies. In her first pregnancy, prenatal testing showed the fetus was homozygous for the deleterious PHYH variant. A miscarriage occurred a few days after a trophoblast biopsy. In the second pregnancy, the fetus was a carrier of the deleterious PHYH variant, and the pregnancy proceeded uneventfully. In the third pregnancy, the fetus was found to be homozygous for the deleterious PHYH variant, and there was a medical termination of the pregnancy. In the fourth pregnancy, the fetus was homozygous for the deleterious PHYH variant, and a baby girl was born. In the subsequent three pregnancies, no prenatal testing was done, and another girl homozygous for the deleterious PHYH variant was born. During all her pregnancies, dietary therapy was essentially unchanged, with monitoring of body weight and plasma PA levels. Despite weight gain (10 kg added during the first 4 to 5 months of the fourth pregnancy), she presented no complications during delivery and postpartum. Ultrasound showed no abnormalities in fetuses with homozygous PHYH deleterious variants. Fetal viability, biometric indices, morphological parameters, and annexes evaluated were all normal. The two affected females were born without special events (notably without shortened metatarsals), but their plasma phytanic acid levels were slightly elevated. The two newborns were fed with phytanic acid-deficient milk and immediately placed on a low‐phytanic acid diet. Their plasma phytanic acid levels were normal at 3 weeks and 4 months at age.

Anesthesia

Symptom exacerbation has been associated with stress and prolonged fasting, and, thus, caution is warranted if a person with adult Refsum disease undergoes anesthesia. In individuals with neuropathy, careful perioperative positioning is necessary to prevent nerve compression. Due to the risk of electrocardiographic changes, perioperative cardiac monitoring is necessary.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Susan Kuranoff BA

Dr. Kuranoff of the Global DARE Foundation has no relevant financial relationships to disclose.
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Kristie DeMarco BS

Ms. DeMarco of the Global DARE Foundation has no relevant financial relationships to disclose.
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Joseph Hacia PhD

Dr. Hacia of the University of Southern California received consulting fees and stocks from Congruence Therapeutics as a consultant and scientific co-founder.
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Editor

Andrea Gropman MD

Dr. Gropman of St. Jude Children's Research Hospital has no relevant financial relationships to disclose.
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Former Authors

Raphael Schiffmann MD
Paul A Watkins MD PhD
Erika Fullwood Augustine MD MS

Patient Profile

Age range of presentation: Typical: 7 months to after 50 years of age
Sex preponderance: Female:male
Heredity: autosomal recessive mode of transmission
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Refsum disease: G60.1
ICD-11: Refsum disease: 5C57.1
OMIM: Refsum disease, classic: #266500

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Adult Refsum disease

Associated Disorders

anosmia
ataxia
cardiac arrhythmia
cardiomyopathy
cataracts
- ichthyosis
- microsmia
- neurogenic deafness
- polyneuropathy
- peripheral neuropathy
- retinitis pigmentosa

Differential Diagnosis

Abetalipoproteinemia
acute demyelinating polyneuropathy (AIDP)
alpha-methylacyl-CoA racemase (AMACR) deficiency
Alström syndrome
amyotrophic lateral sclerosis (ALS)
- Bardet-Biedl syndrome (BBS)
- Batten disease (neuronal ceroid lipofuscinosis)
- Charcot-Marie-Tooth syndrome (CMT)
- Dejerine-Sottas syndrome (DSS)
- Friedreich ataxia (FA)
- hereditary ataxias
- infantile Refsum disease (IRD)
- Kearns-Sayre syndrome (KSS)
- multiple sclerosis (MS)
- peroxisome biogenesis disorders (PBDs)
- PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract)
- retinitis pigmentosa (RP)
- rhizomelic chondrodysplasia punctata (RCDP) types 1, 2, and 3
- Sjögren-Larsson syndrome (SLS)
- sterol carrier protein x (SCPx) deficiency
- Tangier disease
- Tay-Sachs disease
- untreated thiamine deficiency
- Usher syndrome types I, II, and III
- Zellweger spectrum disorder (ZSD)

Also Relevant

Autosomal dominant hereditary ataxias
Childhood movement disorders
Chondrodysplasia punctata
Disorders of peroxisome assembly and function
Horizontal gaze palsy
- Nondominant hereditary ataxias
- Single enzyme defects of peroxisomal beta-oxidation
- Unusual retinopathies

Adult Refsum disease

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical and Laboratory Features of Adult Refsum Disease

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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