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Farber lipogranulomatosis: An unusual presentation in a black child
Farber Lipogranulomatosis'. An Unusual Presentation in a Black Child Lydia Eviatar, MD*, Susan L. SHower, MD~, Krystyna Wisniewski, MDt, Robert S. Feldman, MD*, and Aurora Gochoco, MD*
Ftgure 1.
Soft tissue masses over w m t s are evident.
Farber disease, a rare, inherited condition of lipid metabolism usually appears within the first two months of life. The patients may die in the first few years of life or may live into the second decade. We believe this patient to be the first black American reported with Farber disease. Additionally, the characteristics of the disease in this patient were at variance with previously reported cases. Eviatar L, Sklower SL, W i s n i e w s k i K, F e l d m a n RS, G o c h o c o A. Farber l i p o g r a n u l o m a t o s i s : A n u n u s u a l p r e s e n t a t i o n in a black child. Pediatr N e u r o l 1986; 2:371-4.
Introduction Farber disease [1] is a rare, genetically determined disorder of lipid metabolism. The clinical manifestations, as described by Moser and Chen [2] in a review of 27 patients, vary from severe with demise before age four years to mild with survival into the second decade. The first symptoms of the disease usually appear between two and eight weeks of age. To our knowledge, this patient is the first black American reported with Father disease; the presentation also is significantly different from previously described cases
[2-51. Case Report This 51/2-year-old black female, the 3,180 gm product of a 15-
From the *Department of Pediatric Neurology; Long Island Jewish Medical Center, Schneider Children's Hospital; New Hyde Park, New York; tInstitute for Basic Research and Developmental Disabilities; 1050 Forest Hill Road; Staten Island, New York.
Figure 2.
Soft tissue masses are present over dorsum o f both feet.
year-old G1 P0 mother and a 22-year-old nonconsanguineous father, was delivered by cesarean section at 42 weeks gestation because of lack of progression of labor and fetal distress. Briefcyanosis associated with a nuchal cord was present and was corrected with release of the nuchal cord and administration of supplemental oxygen. Otherwise, the condition of the newborn was good and she was discharged after three days. The pregnancy was uncomplicated except for "migraine" headaches which were treated with an unknown medication and vaginal spotting which occurred at about the seventh month. The father was a known drug abuser (specific drugs unknown). There was
Communications should be addressed to: Dr. Eviatar; Long Island Jewish Medical Center, Schneider Children's Hospital; Department of Pediatric Neurology; New Hyde Park, NY 10042. Received June 17, 1986; accepted October 1, 1986.
Eviatar et al: Farber Lipogranulomatosis
371
Ftgure 3. The patient manifests poor head control, emaciation, dt~td contractures, as well as soft tissue masses over distal joints.
no family history of neurologic or neurocutaneous disorders. The child was relatively free of major illnesses. Developmental milestones were normal until about 2 l/z years of age. She walked at 8 months of age, said words at 9-12 months, and used short sentences at 2 years of age. Toilet training was accomplished at 21 months of age. She began running and riding a tricycle at 2 years of age. Six months later, the mother noticed increasing unsteadiness of gait which was initially intermittent. Nearly continuous tremors and jerks of the extremities began, accompanied by disturbances in motor coordination, and diminished progress in speech. Over the next several months, there was loss of previously acquired motor skills, including tricycle riding, and deterioration of language. Drooping of both eyelids was observed. After age 3 years, behavioral changes occurred, manifested by frequent temper tantrums, emotional lability, hyperactivity, and aggressiveness. The patient was examined initially by us at 4 years of age. She had moderate mental retardation, extreme hyperactivity, bilateral ptosis, excessive drooling, and dysarthria. Most prominent were continuous involuntary movements characterized by tremor and polymyoclonia. There were facial twitches, opsoclonus, and continuous head and trunk titubations to the extent that ambulation was impossible. The following tests were normal: liver enzymes, serum and urine amino acids, cerebrospinal fluid, bone marrow evaluation, ~TFe uptake, urine HVA and VMA, and eye examination. Computed tomography (CT) scans of the head and chest failed to demonstrate any mass or other abnormality. However, rectal biopsy demonstrated focal clusters of foamy histiocytes with PAS material in the lamina propria. Electroencephalography (EEG) revealed bursts of generalized, bilaterally synchronous paroxysms of 3-31/2 Hz slow wave activity which were often associated with low amplitude spikes or sharp waves, more prominent in the posterior regions. This finding was superimposed on a slow background during wakefulness. Treatment was initiated with clonazepam (1.5 mg/day in divided doses) which decreased the polymyoclonia and tremors to the point that she was
372
PEDIATRIC NEUROLOGY
Vol. 2 No. 6
Ftgure 4.
Fact~ dtjOlegia is c/early demonstrated.
able to ambulate independently. At age 41/2 years, she began having generalized tonic-clonic seizures and was placed on phenytoin. By this time she had developed signs of spasticity with increased muscle tone and hyperreflexia; she could walk only with support. Over the ensuing year, she developed soft tissue masses over the dorsum of her hands and feet which were fixed and doughy in consistency and situated over the tendons. They were painless. Progressive dementia was observed. She continued to have seizures, as well as recurrent respiratory infections and aspiration pneumonia. Since 5 years of age, she has required a wheelchair. Currently, her deep tendon reflexes have decreased, achilles reflexes are absent, and patellar reflexes are barely elicitable. There is cogwheel rigidity of the upper and lower extremities. Bilateral ptosis and facial weakness suggest bilateral facial diplegia. She also has progressive bulbar dysfunction. Recent CT and magnetic resonance imaging (MRI) scans depicted diffuse cortical atrophy; however, BAER and VER are normal. There is marked slowing of motor and sensory nerve conduction velocities. An open biopsy of the soft tissue tumor over the wrist was performed. Analysis of the tissue revealed an increase in the nonesterified ceramide content to 9.5 % of total lipid. (All determinations were performed by Dr. Hugo Moser; Baltimore, MD). A ceramidase assay of skin fibroblasts demonstrated a level of 0.05 nmol/mg protein/hr. Three normal controls ranged between 2.212.94 nmol/mg protein/hr. Other lysosomal enzymes including hexosaminidase, arylsulfatase, and 3-galactosidase were normal. Endoplasmic vacuoles in the skin were filled with curvilinear type bodies (Figs 5,6). Abnormalities in the mitochondrial endoplasmic reticulum and lysosomes were observed in the fibroblasts and fibrocysts.
Discussion
The specific diagnosis of Farber disease depends
The type of neurologic involvement differs from the previously described patients not only because of the rapid mental deterioration accompanied by polymyoclonia and cerebellar signs but also by the late onset and protracted course. Infantile spasms were reported in 2 of 27 patients, 10 of whom had generalized seizures. However, progressive dementia, cerebellar signs, generalized polymyoclonus, and opsoclonus were not reported. The histologic picture of the rectal biopsy that demonstrated swollen histiocytes with PAS positive material in subintimal location is consistent with previous reports. The bone marrow was not involved in our patient as in most other cases described; other findings, such as cataracts, were absent. According to Moser and Chen, the nervous system has been abnormal in all but two autopsied patients [2]. The major accumulation of storage material was found in neuronal cytoplasm, particularly prominent in the anterior horn cells in the spinal cord. Large cell involvement of brainstem nuclei, basal ganglia, cerebellum, and to a lesser degree, cortical neurons also was present. It is well documented that ceramide is vital in cerebral sphingolipid metabolism. Thus, it is not unexpected to find neuronal storage in this disease. It is Figure 5. (A) Fibroblasts with distended endoplasmic vacuoles and curvilinear-type bodies as seen with low magnification. (t3) Same charactert)tics with high magnification.
upon demonstration of a deficiency of acid ceramidase in cultured skin fibroblasts or in white blood cells. This patient fulfills these criteria. Moreover, ceramide content in the subcutaneous nodules is markedly increased. In addition, the presence of curvilinear inclusion bodies on electron microscopy of the skin also is suggestive of ceramide storage at the subcellular level, as demonstrated in other lipidoses in which ceramide accumulation occurs [4,6,7]. The clinical course of the illness is characterized by progressive hoarseness, painful and swollen joints, periarticular and subcutaneous nodules, and pulmonary infiltration [1,2,5]. In this patient, the neurologic findings of progressive dementia, dysarthria, drooling, generalized polymyoclonus, ataxia, and tremors preceded the appearance of swollen joints and subcutaneous nodules by at least two years. Both the clinical course and the severity of the EEG changes indicate that the lipid storage in this patient began in the cortical and subcortical areas of the brain, cerebellum, and in the brainstem about two years prior to the involvement of cutaneous tissues and three years prior to the vocal cord involvement. The delayed nerve conduction velocities are supportive evidence of neuropathy or lower motor neuron involvement.
Figure 6. (A) Farber bodies as seen wtth low magnificatton. (B) Same characteristics seen with high magnification.
Eviatar et ah Farber Lipogranulomatosis
373
more difficult to explain the variability of expression and the susceptibility of specific organ involvement because the enzyme defect in vitro appears the same in all patients. References
[1] Farber S, Cohen J, Uzman LL. Lipogranulomatosis: A new lipoglycoprotein "storage" disease. Mt SinaiJ Med 1957;24:816. [2] Moser H, Chen W. Ceramidase deficiency: Farber's lipogranulomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson, DS, Goldstein JL, Brown MS, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1982;820. [3] McKusick VA. Mendelian inheritance in man. Baltimore: Johns Hopkins Press, 1982;709.
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PEDIATRIC NEUROLOGY
Vol. 2 No. 6
[4] Burck U, Moser HW, Goebel HH, Grutner R, Held KR. A case of lipogranulomatosis Farber: Some clinical and ultrastructural aspects. EurJ Pediatr 1985; 143:203-8. [5] Prensky AL. Farber disease. In: Swaiman KF, Wright FS, eds. The practice of pediatric neurology. St. Louis: CV Mosby, 1982: 539-42. [6] Schmoeckel C, Holfeld M. A specific ultrastructural market for disseminated lipogranulomatosis (Farber). Acta Derm Res 1979; 266:187-96. [7] Schoeckel C. Subtle clues to diagnosis of skin diseases by electron microscopy. "Farber bodies" in disseminated lipogranulomatosis (Farber's disease). Am J Dermatopathol 1980;2:153-6.
Ftgure 1.
Soft tissue masses over w m t s are evident.
Farber disease, a rare, inherited condition of lipid metabolism usually appears within the first two months of life. The patients may die in the first few years of life or may live into the second decade. We believe this patient to be the first black American reported with Farber disease. Additionally, the characteristics of the disease in this patient were at variance with previously reported cases. Eviatar L, Sklower SL, W i s n i e w s k i K, F e l d m a n RS, G o c h o c o A. Farber l i p o g r a n u l o m a t o s i s : A n u n u s u a l p r e s e n t a t i o n in a black child. Pediatr N e u r o l 1986; 2:371-4.
Introduction Farber disease [1] is a rare, genetically determined disorder of lipid metabolism. The clinical manifestations, as described by Moser and Chen [2] in a review of 27 patients, vary from severe with demise before age four years to mild with survival into the second decade. The first symptoms of the disease usually appear between two and eight weeks of age. To our knowledge, this patient is the first black American reported with Father disease; the presentation also is significantly different from previously described cases
[2-51. Case Report This 51/2-year-old black female, the 3,180 gm product of a 15-
From the *Department of Pediatric Neurology; Long Island Jewish Medical Center, Schneider Children's Hospital; New Hyde Park, New York; tInstitute for Basic Research and Developmental Disabilities; 1050 Forest Hill Road; Staten Island, New York.
Figure 2.
Soft tissue masses are present over dorsum o f both feet.
year-old G1 P0 mother and a 22-year-old nonconsanguineous father, was delivered by cesarean section at 42 weeks gestation because of lack of progression of labor and fetal distress. Briefcyanosis associated with a nuchal cord was present and was corrected with release of the nuchal cord and administration of supplemental oxygen. Otherwise, the condition of the newborn was good and she was discharged after three days. The pregnancy was uncomplicated except for "migraine" headaches which were treated with an unknown medication and vaginal spotting which occurred at about the seventh month. The father was a known drug abuser (specific drugs unknown). There was
Communications should be addressed to: Dr. Eviatar; Long Island Jewish Medical Center, Schneider Children's Hospital; Department of Pediatric Neurology; New Hyde Park, NY 10042. Received June 17, 1986; accepted October 1, 1986.
Eviatar et al: Farber Lipogranulomatosis
371
Ftgure 3. The patient manifests poor head control, emaciation, dt~td contractures, as well as soft tissue masses over distal joints.
no family history of neurologic or neurocutaneous disorders. The child was relatively free of major illnesses. Developmental milestones were normal until about 2 l/z years of age. She walked at 8 months of age, said words at 9-12 months, and used short sentences at 2 years of age. Toilet training was accomplished at 21 months of age. She began running and riding a tricycle at 2 years of age. Six months later, the mother noticed increasing unsteadiness of gait which was initially intermittent. Nearly continuous tremors and jerks of the extremities began, accompanied by disturbances in motor coordination, and diminished progress in speech. Over the next several months, there was loss of previously acquired motor skills, including tricycle riding, and deterioration of language. Drooping of both eyelids was observed. After age 3 years, behavioral changes occurred, manifested by frequent temper tantrums, emotional lability, hyperactivity, and aggressiveness. The patient was examined initially by us at 4 years of age. She had moderate mental retardation, extreme hyperactivity, bilateral ptosis, excessive drooling, and dysarthria. Most prominent were continuous involuntary movements characterized by tremor and polymyoclonia. There were facial twitches, opsoclonus, and continuous head and trunk titubations to the extent that ambulation was impossible. The following tests were normal: liver enzymes, serum and urine amino acids, cerebrospinal fluid, bone marrow evaluation, ~TFe uptake, urine HVA and VMA, and eye examination. Computed tomography (CT) scans of the head and chest failed to demonstrate any mass or other abnormality. However, rectal biopsy demonstrated focal clusters of foamy histiocytes with PAS material in the lamina propria. Electroencephalography (EEG) revealed bursts of generalized, bilaterally synchronous paroxysms of 3-31/2 Hz slow wave activity which were often associated with low amplitude spikes or sharp waves, more prominent in the posterior regions. This finding was superimposed on a slow background during wakefulness. Treatment was initiated with clonazepam (1.5 mg/day in divided doses) which decreased the polymyoclonia and tremors to the point that she was
372
PEDIATRIC NEUROLOGY
Vol. 2 No. 6
Ftgure 4.
Fact~ dtjOlegia is c/early demonstrated.
able to ambulate independently. At age 41/2 years, she began having generalized tonic-clonic seizures and was placed on phenytoin. By this time she had developed signs of spasticity with increased muscle tone and hyperreflexia; she could walk only with support. Over the ensuing year, she developed soft tissue masses over the dorsum of her hands and feet which were fixed and doughy in consistency and situated over the tendons. They were painless. Progressive dementia was observed. She continued to have seizures, as well as recurrent respiratory infections and aspiration pneumonia. Since 5 years of age, she has required a wheelchair. Currently, her deep tendon reflexes have decreased, achilles reflexes are absent, and patellar reflexes are barely elicitable. There is cogwheel rigidity of the upper and lower extremities. Bilateral ptosis and facial weakness suggest bilateral facial diplegia. She also has progressive bulbar dysfunction. Recent CT and magnetic resonance imaging (MRI) scans depicted diffuse cortical atrophy; however, BAER and VER are normal. There is marked slowing of motor and sensory nerve conduction velocities. An open biopsy of the soft tissue tumor over the wrist was performed. Analysis of the tissue revealed an increase in the nonesterified ceramide content to 9.5 % of total lipid. (All determinations were performed by Dr. Hugo Moser; Baltimore, MD). A ceramidase assay of skin fibroblasts demonstrated a level of 0.05 nmol/mg protein/hr. Three normal controls ranged between 2.212.94 nmol/mg protein/hr. Other lysosomal enzymes including hexosaminidase, arylsulfatase, and 3-galactosidase were normal. Endoplasmic vacuoles in the skin were filled with curvilinear type bodies (Figs 5,6). Abnormalities in the mitochondrial endoplasmic reticulum and lysosomes were observed in the fibroblasts and fibrocysts.
Discussion
The specific diagnosis of Farber disease depends
The type of neurologic involvement differs from the previously described patients not only because of the rapid mental deterioration accompanied by polymyoclonia and cerebellar signs but also by the late onset and protracted course. Infantile spasms were reported in 2 of 27 patients, 10 of whom had generalized seizures. However, progressive dementia, cerebellar signs, generalized polymyoclonus, and opsoclonus were not reported. The histologic picture of the rectal biopsy that demonstrated swollen histiocytes with PAS positive material in subintimal location is consistent with previous reports. The bone marrow was not involved in our patient as in most other cases described; other findings, such as cataracts, were absent. According to Moser and Chen, the nervous system has been abnormal in all but two autopsied patients [2]. The major accumulation of storage material was found in neuronal cytoplasm, particularly prominent in the anterior horn cells in the spinal cord. Large cell involvement of brainstem nuclei, basal ganglia, cerebellum, and to a lesser degree, cortical neurons also was present. It is well documented that ceramide is vital in cerebral sphingolipid metabolism. Thus, it is not unexpected to find neuronal storage in this disease. It is Figure 5. (A) Fibroblasts with distended endoplasmic vacuoles and curvilinear-type bodies as seen with low magnification. (t3) Same charactert)tics with high magnification.
upon demonstration of a deficiency of acid ceramidase in cultured skin fibroblasts or in white blood cells. This patient fulfills these criteria. Moreover, ceramide content in the subcutaneous nodules is markedly increased. In addition, the presence of curvilinear inclusion bodies on electron microscopy of the skin also is suggestive of ceramide storage at the subcellular level, as demonstrated in other lipidoses in which ceramide accumulation occurs [4,6,7]. The clinical course of the illness is characterized by progressive hoarseness, painful and swollen joints, periarticular and subcutaneous nodules, and pulmonary infiltration [1,2,5]. In this patient, the neurologic findings of progressive dementia, dysarthria, drooling, generalized polymyoclonus, ataxia, and tremors preceded the appearance of swollen joints and subcutaneous nodules by at least two years. Both the clinical course and the severity of the EEG changes indicate that the lipid storage in this patient began in the cortical and subcortical areas of the brain, cerebellum, and in the brainstem about two years prior to the involvement of cutaneous tissues and three years prior to the vocal cord involvement. The delayed nerve conduction velocities are supportive evidence of neuropathy or lower motor neuron involvement.
Figure 6. (A) Farber bodies as seen wtth low magnificatton. (B) Same characteristics seen with high magnification.
Eviatar et ah Farber Lipogranulomatosis
373
more difficult to explain the variability of expression and the susceptibility of specific organ involvement because the enzyme defect in vitro appears the same in all patients. References
[1] Farber S, Cohen J, Uzman LL. Lipogranulomatosis: A new lipoglycoprotein "storage" disease. Mt SinaiJ Med 1957;24:816. [2] Moser H, Chen W. Ceramidase deficiency: Farber's lipogranulomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson, DS, Goldstein JL, Brown MS, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1982;820. [3] McKusick VA. Mendelian inheritance in man. Baltimore: Johns Hopkins Press, 1982;709.
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PEDIATRIC NEUROLOGY
Vol. 2 No. 6
[4] Burck U, Moser HW, Goebel HH, Grutner R, Held KR. A case of lipogranulomatosis Farber: Some clinical and ultrastructural aspects. EurJ Pediatr 1985; 143:203-8. [5] Prensky AL. Farber disease. In: Swaiman KF, Wright FS, eds. The practice of pediatric neurology. St. Louis: CV Mosby, 1982: 539-42. [6] Schmoeckel C, Holfeld M. A specific ultrastructural market for disseminated lipogranulomatosis (Farber). Acta Derm Res 1979; 266:187-96. [7] Schoeckel C. Subtle clues to diagnosis of skin diseases by electron microscopy. "Farber bodies" in disseminated lipogranulomatosis (Farber's disease). Am J Dermatopathol 1980;2:153-6.