Introduction
There are more than 50 rare lysosomal disorders which are mainly autosomal recessive appendages. Farber disease is one of the lysosomal abnormalities that can lead to death in childhood through various conflicts in nervous system. Lysosomal disease in the Iranian population are relatively common due to the relatively common family marriage. An outbreak has been reported in one out of 8,000 newborns.
Farber disease is a rare lysosomal storage disease. Lysosomes are an intracellular digestive system responsible for subcellular organs and membrane organelles that originate from a golgi apparatus. This organelle has a body size range of 0.2 to 0.8 micrometers, with an average size of 0.4 microns, and like all the other intracellular organelles has membrane, with the difference that its membrane is a single layer. The membrane is similar to the plasma membrane of the cell, but it is thicker than the mitochondrial membrane. Lysosomes contain bags containing acidic hydrolysis enzymes. This organ is presented in animal, plant, and even single-cell creatures. However, bacteria lack it. Due to the presence of enzymes in their lysosomes, they can destroy the cells and membrane when their membrane is torn and its content removes.
The enzymes in the lysosomes can act well at an acid PH of about 4.5 to 5. In the lysosomal membrane, there are APA-dependent protein pumps that by using protein energy, they enter H+ into the lysosome to make acidic environment with a pH of about 4.5 to 5, providing acidic conditions for the lysosomal hydrolysis enzymes and maintaining the pH gradient in the lysosomal membrane. The lysosomal hydrolysis enzymes do not affect their membrane. Using proton energy, H+ is introduced into lysosome to create an acidic pH of about 4.5 to 5.
Lysosomal enzymes: lysosomal enzymes have hydrolysis act, and these enzymes are active in acidic pH. Appropriate pH for their activity is about 4.5 to 5. About 50 types of acid hydrolysis have been identified that one of the major lysosomal enzymes is acid phosphatase enzyme. This enzyme has glycoprotein structure and is located within the lysosome. Lysosomal storage diseases are caused by the accumulation of waste materials within organelles.
The variety of these diseases is very wide in terms of the type of material stored in the particular organ and the age of the onset of symptoms, and various phenotypes have been reported even among one family members. Symptoms have been reported for the first time in 1880 and the division of the disease before its biochemical and genetic study was reported in 1955. The disease is the result of impairment in the process of enzyme activity and accumulation of waste materials in target organs. With regard to enzyme diversity, about 40 different types of lysosomes, such as Gaucher`s disease, Niemann-Pick disease, various types of mucopolysaccharidosis, including Farber disease, are known.
Particular symptoms of Farber disease include granulomas around the joints, subcutaneous nodules and violent sound, silent crying, pain, arthritis, large liver and spleen, developmental delay, and respiratory failure due to granulomatous lesions in the respiratory tract. Based on symptoms, Farber is divided into 7 types:
Type one: this type is the classic form of the disease and the most common form.
Type two and three: they are rare and symptoms of the disease are milder than other types.
Type four and five: they appear with wide-spread neurological symptoms such as central nervous and peripheral disturbances, myoclonus, and evolutionary delays.
Type six and seven: are very rare.
Severe type of the disease: patients are normal at birth and have symptoms during the first few weeks or months of life (in infancy) with painful swelling and stiffness of the joints, palpable subcutaneous nodules in the skin around the affected joints, rough crying, interstitial infiltration pulmonary edema, developmental delay, malnutrition and growth disturbances, intermittent fever and significant excitability. In some patients, the enlargement of the liver, corneal opacity, and red maroon smear appears in the macula [1]. Increasing the number and size of nodules and developing granuloma in the pharynx and larynx causes difficulty in swallowing and airway obstruction, and the patient`s death occurs up to 2 years of age due to pulmonary complications.
Milder and rare types of disease: in this type of disease, the knee contractures, wrists, and fingers have a bending position and subcutaneous nodules are found in patients with normal and non-inflammatory liver and lung function. The patient`s life continues until early childhood or late adolescence, and death occurs due to severe malnutrition and pneumonia. In a small number of patients, the size of the liver and spleen and severe pulmonary infiltration of the neonate period are observed without subcutaneous nodules and death occurs within a few months. Another rare form of delayed evolution is the regression of function from 12 to 24 month that occurs with imbalance, tremor, stiffness, seizure, and reduced tendon reflexes, stiffness of the joints and subcutaneous nodules, and the patient`s death occurs at around 3 years of age.
The two forms of the disease are as follows:
Non-classic form: the patient has normal birth and neonatal period. The patients is often irritable during infancy, accompanied by crying and screaming attack without any obvious reason. Then, progressive neural analysis occurs along with muscle stiffness. The patient`s hand are punched and the legs are in a straight and right (extension) position. Sometimes, the patient show irritability and muscle spasms from the time of the birth. Vomiting may be an early symptom. Also, these patients are very sensitive to sound, light or touch, and with these stimuli, they experience muscular stiffness and start screaming. There is also a risk of fever without explanation or seizure, retardation, or the reversal psycho-motor development. The patient has toughness and opisthotonos, and his upper limbs are in the bent positon, and the lower extremities in all joints are in the right position, close to the axis of the body. Reduced tendon reflexes, rapid deterioration of mental and motor status, slow response of the pupils to light, and mild disorientation of the visual disc are also seen. Often, a small head and sometime large head or hydrocephalus is seen, and the patient dies at the age of two.
Non-classic type with late occurrence: in most cases, the disease occurs about the age of 10. It occurs in small cases between the ages of 20 and 30. In adulthood form, the appearance of the disease is between the ages of 30 to 35 with weak spasticity and progression of lower limbs or damage to peripheral nerves and dementia has been observed.
Classic form: this is the severe type of disease that was described above. Swelling and nodules around the joints and the enlargement of the liver and spleen are shown in figure 1.

Figure 1) Patient with Farber

Diagnostic method: enzyme examination in fibroblasts, biopsy of skin nodules, and genetic evaluation of the Farber disease or lipogranulomatosis due to homozygous mutation or compound heterozygote mutation in the chromosome 8 acid encoding gene are diagnostic methods.
Patients and methods
In this report, 6 patients with Farber disease or lipogranulomatosis diagnosed in the last seven years were introduced. Clinical symptoms in most patient included joint stiffness and pain, weak and silent crying, granulomas and nodules around the joints. Five patients were girl and only one of them was a boy that the boy had died at birth. Three patients had larger liver and spleen, and currently only 3 patients are alive. Four gene mutations were reported with genetic evaluation of patients. Table 1 represents age of the disease, a summary of the clinical symptoms and the outcome of the mutations (Table 1).

Table 1) Summary of clinical symptoms and the results of molecular investigations in 6 patients with Farber Disease

 

Discussion
Farber disease is a rare and fetal disease with autosomal recessive inheritance, first reported by Sidney Farber et al. in 1957 [2]. Abul Haj et al. in 1962 reported a case of illness by observing the storage of ceramide in the Pediat journal [3]. The mutation in ASAH1 was reported between 1996 and 2001 by Koch et al. which was a homoallelic mutation [4]. Bar et al. in 200l, identified six new mutations in the ASAH1 gene as a point mutation that displaced an amino acid [5].
Classification of the disease is based on the enzymatic level below 10% normal and the accumulation of waste materials in target organs. Metabolic examination in 4 patients` fibroblasts showed that although the leading proteins of acid ceramidase were synthesized in them, mature mutated ceramidase rapidly became proteolyzed. A patient with Farber disease severely suffered from hydrops fetalis and died at 3 days [6]. Acid ceramidase is a lysosomal soluble enzyme that is responsible for ceramide degradation. Serious acid ceramidase deficiency (less than 10%) results in gradual accumulation of ceramide in most tissues. Alvez et al. reported two destructive mutations in a compound heterozygote in the ASAH1 gene which was associated with a severe phenotype of the patient by completely removing the acid ceramidase [7]. Ben-Yoseph et al. reported a deficiency of acid ceramidase in Farber disease in 1989 [8].
Patients suffer from rigidity, joint softness, bulging nodules under the skin, voice dryness due to laryngeal involvement. With disease progression, patients suffer from heart disease, respiratory symptoms, and central nervous system defects. Similar to other lysosomal reserve disease, in terms of severity, they show a range of symptoms.

Conclusion
Farber disease is one of the rare diseases of lysosomal storage of which only 80 cases have been reported. The study reviewed and reported six patients, with four new mutations. Exclusive treatment is not available right now. Currently only supportive treatment can be used. Corticosteroid is used to reduce joint pain. In mild forms of disease, bone marrow transplantation or hematopoietic stem cell transplantation lead to relative improvement in non-neuropathic symptoms. The inheritance of autosomal recessive disease and the risk of recurrence in subsequent pregnancy is 25%. The need for genetic evaluation is felt in patients and in pregnancies. In case of finding a mutation, it can be checked during pregnancy and in case of fetus involvement, pregnancy stoppage is recommended in Iran.

Acknowledgements: The case was not found by the authors.
Ethical permissions: The case was not found by the authors.
Conflict of interests: The case was not found by the authors.
Financial support: This study was supported by Sarem Cell Research Center.
Contribution of authors: Fatemeh Hadipour (First author), author of the article/main author/statistical analyst/author of discussion (%30); Zahra Hadipour (Second author), author of the article/helper author/author of discussion (%20); Alireza Tavasoli (Third author), author of the article/helper author (%20); Yousef Shafeghati (Fourth author), author of the article/methodology/main author/author of discussion (%30).