Alternative titles; symbols
SNOMEDCT: 79935000; ORPHA: 333; DO: 0050464;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p22 | Farber lipogranulomatosis | 228000 | Autosomal recessive | 3 | ASAH1 | 613468 |
A number sign (#) is used with this entry because of evidence that Farber lipogranulomatosis (FRBRL) is caused by homozygous or compound heterozygous mutation in the gene encoding acid ceramidase (ASAH1; 613468) on chromosome 8p22.
Farber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (summary by Alves et al., 2013).
In the few reported cases of Farber disease, manifestations appeared in the first few weeks of life and consisted of irritability, hoarse cry, and nodular, erythematous swellings of the wrists and other sites, particularly those subject to trauma. Severe motor and mental retardation was evident. Death occurred by 2 years of age. The histologic appearance was granulomatous. In the nervous system, both neurons and glial cells were swollen with stored material characteristic of nonsulfonated acid mucopolysaccharide (Abul-Haj et al., 1962). Parental consanguinity had not been identified. However, in 1 case parents had the same family name in ancestors, and 2 of 3 families seen at Children's Hospital, Boston, were of Portuguese extraction. The family with 2 affected sibs had father from the Azores Islands and mother from the Madeira Islands. The parents of the other family were both born in the Azores (Crocker et al., 1967).
Clausen and Rampini (1970) proposed that an enzymatic defect in glycolipid degradation is the basic fault. Sugita et al. (1972) suggested that the basic defect is a deficiency of acid ceramidase (AC), also called N-acylsphingosine amidohydrolase (ASAH), which normally catalyzes the synthesis and degradation of ceramide. No activity of this enzyme could be demonstrated in kidney and cerebellum.
Antonarakis et al. (1984) described 2 sibs, a 12-week-old girl with classic severe features (subcutaneous periarticular nodules, hoarse cry, failure to thrive, and respiratory insufficiency) and a 10-week-old boy, who presented earlier, with clinical features suggestive of malignant histiocytosis. They died at 6 months and at 12 weeks, respectively. The girl also had hepatosplenomegaly, a relatively unusual feature of Farber disease; of 27 reported cases, 7 had hepatomegaly and 1 had splenomegaly. Thus, Farber disease should be considered in infants with seeming malignant histiocytosis. Because of the 25% recurrence risk and ability to make prenatal diagnosis, assay of ceramidase is important in such cases.
Pellissier et al. (1986) studied 2 severely affected sibs born of consanguineous Tunisian parents. Involvement of both the central and peripheral nervous system was documented. Macular cherry red spots were observed in 1.
Moser et al. (1989) identified 5 types of Farber lipogranulomatosis. In the classic type 1, the diagnosis can be made almost at a glance by the triad of subcutaneous nodules, arthritis, and laryngeal involvement. When 1 aspect is missing, the possibility of juvenile rheumatoid arthritis, multicentric reticulohistiocytosis, or juvenile hyaline fibromatosis (228600) may be entertained, but ceramidase levels are normal in all of these conditions. Patients with types 2 and 3 survive longer. Liver and lung appear not to be involved. Normal intelligence in many of these patients and the postmortem findings suggest that brain involvement is limited or missing entirely. Moser et al. (1989) stated that several patients with type 3 were 'in relatively stable condition near the end of the second decade.' Type 4 patients present with hepatosplenomegaly and severe debility in the neonatal period and all die before 6 months of age. Massive histiocytic infiltration of liver, spleen, lungs, thymus, and lymphocytes is found at autopsy.
Antonarakis et al. (1984) reported patients with severe type 4 lipogranulomatosis. Their case 1 had not been recognized even after postmortem study, and the diagnosis of Farber disease was considered only in retrospect when subcutaneous nodules were noted in a subsequently born sib.
Type 5 lipogranulomatosis, described by Zarbin et al. (1985) and Eviatar et al. (1986), is characterized particularly by psychomotor deterioration beginning at age 1 to 2.5 years. The family of Zarbin et al. (1985) included 2 affected sisters from a marriage of a Korean national and a Caucasian female; the affected girls may represent a genetic compound. As in the case of Pellissier et al. (1986), macular cherry red spots were noted. The patient of Eviatar et al. (1986) was a black child.
Qualman et al. (1987) described a family in which 1 child, a 3-month-old boy, presented with only hepatosplenomegaly and had a fulminant clinical course suggestive of malignant histiocytosis. The second child, a 5.5-month-old girl, had the typical clinical presentation of Farber disease, with hoarseness and painful swollen joints. Visceral involvement was prominent in both, and included a newly described nephropathy with elevated urine ceramide levels. Liver and spleen contained massive histiocytic infiltrates in association with elevated ceramide levels. Lymph nodes also contained histiocytic infiltrates but without the sinusoidal involvement typical of proliferative histiocytic disorders.
Nowaczyk et al. (1996) described a 16-week-old female infant with the rare type IV Farber lipogranulomatosis featuring hepatosplenomegaly, macular cherry red spot, and subcutaneous nodules. The patient developed liver dysfunction with jaundice and ascites and myelophthisic anemia because of infiltration of the bone marrow with storage cells. Direct assay of skin fibroblasts confirmed the diagnosis of ceramidase deficiency.
Kattner et al. (1997) reported a severe case of Farber lipogranulomatosis presenting as nonimmune hydrops fetalis. Prenatal ultrasound at 26 weeks' gestation showed hydrops fetalis with hepatosplenomegaly. The infant died 3 days after birth. Postmortem examination showed edema and multiple white nodules disseminated throughout the body that consisted of storage macrophages and fibrosis. Splenic tissue showed an accumulation of ceramide, and ceramidase activity was profoundly reduced in patient tissues. The parents were unrelated and a prior pregnancy had resulted in early spontaneous abortion.
Bonafe et al. (2016) reported 3 Iranian sibs, aged 40, 58 and 60 years, with severe adult-onset peripheral osteolysis and a history of episodic fever and pain in childhood. The 40-year-old sib had episodes of fever and pain starting at 3 years of age. He also developed subcutaneous nodules on the ears and over the wrist, elbow and knee joints. He also developed hoarseness. The episodes subsided, and he had joint pain starting at age 12 years. At 40 years of age, he had limitation of movement of knee joints and flexion of the toes. His hands and toes were shortened and the skin over his hands was redundant. X-rays showed severe osteolysis of the distal radius, ulna, metacarpal bones, and phalanges. His feet were similarly affected. His 2 older sibs had short hands and redundant skin. They also had hoarseness, episodic pain and fever, and ear nodules in childhood. None of the sibs had neurologic abnormalities.
Bao et al. (2020) reported a 25-year-old woman with osteolytic changes in the hands and toes. Nodules were noted on her scalp and paravertebral region when she was 3 months of age and she also had a hoarse voice. Within 4 years, the nodules progressed to her eyelids, ears, hands, wrists, elbows, and knee joints. At 19 years of age, her fingers and toes began to shorten and her skin started to overlap. She also had bilateral flexion contractures and reduced muscle and subcutaneous fat. Hand x-rays showed osteoporosis and severe osteolytic changes in the bilateral phalanges, metacarpi, distal ulnae, and radii. Visualization of the larynx revealed vocal cord thickening with nodules. She had a similarly affected brother, who had severe joint deformities and redundant skin, but who did not undergo genetic testing.
Ben-Yoseph et al. (1989) used N-laurylsphingosine deacylase as a substrate for studying the usefulness of plasma specimens for diagnosis and carrier detection of Farber disease. This made a highly sensitive assay because the substrate is cleaved by acid ceramidase at a much faster rate than are other substrates.
In a review of acid ceramidase deficiency, Yu et al. (2018) noted that in some patients with Farber disease hematopoietic stem cell transplantation was shown to improve voice hoarseness, subcutaneous nodules, and joint pain, but did not appear to reverse neurologic involvement.
Farber lipogranulomatosis shows autosomal recessive inheritance (summary by Alves et al., 2013).
Farber disease is caused by mutations in the ASAH1 gene, which Li et al. (1999) mapped to chromosome 8p22-p21.3.
In a patient with Farber disease, Koch et al. (1996) identified a homoallelic thr222-to-lys (T222K; 613468.0001) in the ASAH1 gene.
Bar et al. (2001) identified 6 novel mutations in the ASAH1 gene causing Farber disease: 3 point mutations resulting in single amino acid substitutions (see, e.g., 613468.0003-613468.0004), 1 intronic splice site mutation resulting in exon skipping, and 2 point mutations leading to occasional or complete exon skipping. The last 2 mutations occurred in adjacent nucleotides and led to abnormal splicing of the same exon. Metabolic labeling studies in fibroblasts of 4 patients showed that even though acid ceramidase precursor protein was synthesized in these individuals, rapid proteolysis of the mutated, mature acid ceramidase occurred within the lysosome.
In a patient with severe Farber disease resulting in hydrops fetalis and death at age 3 days (Kattner et al., 1997), Alves et al. (2013) identified compound heterozygosity for 2 null mutations in the ASAH1 gene (613468.0008 and 613468.0009). The severe phenotype correlated with a complete loss of the full-length protein.
In 3 Iranian sibs, aged 40, 58 and 60 years, with Farber disease, Bonafe et al. (2016) identified compound heterozygous mutations in the ASAH1 gene (613468.0012-613468.0013). The mutations were identified by whole-exome sequencing and segregated with disease in the family. Acid ceramidase enzyme activity in fibroblasts from 2 of the sibs were reduced to 7 to 8% of control levels.
In a 25-year-old woman with Farber disease, Bao et al. (2020) identified compound heterozygous mutations in the ASAH1 gene. The mutations were identified by sequencing of the ASAH1 gene. The patient had osteolytic changes of the hands and toes and a history of nodules since infancy, hoarseness, joint swelling, and bone pain. She had a similarly affected brother who did not undergo genetic testing.
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