Multiple subcutaneous nodules with delayed developmental milestones in a child

Question

What is your diagnosis?

Answer

Other investigations

Whole exome sequencing (genetic analysis) revealed a missense mutation in the ASAH1 gene. The variation was the amino acid substitution of arginine for tryptophan at codon 185 in exon 8 (c.553T>C; p.Trp185Arg) and a diagnosis of Farber disease (FD) was made.

Discussion

FD is a lysosomal storage disorder caused by acid ceramidase (EC3.5.1.23) deficiency, which deacetylates ceramide to sphingosine and free fatty acid, and is deficient as a result of these mutations and lead to widespread ceramide accumulation, affecting various organs and accompanying clinical symptoms.¹ FD is divided into seven subgroups, including the classical variant type 1, intermediate type 2, mild type 3, neonatal-visceral variant type 4, neurological progressive variant type 5, combined FD and Sandhoff disease type 6 and prosaposin deficiency type 7.¹ Subcutaneous nodules, arthritis and hoarseness of voice are the typical triad of symptoms that appear in FD.² Among the ocular findings, the cherry red spot in the macula is the most typical finding and others are retinal and corneal opacities and macular degeneration.³ Pathologically, the subcutaneous nodules consist of granulomatous lesions that show an array of histological changes, depending on the stage of the disease. The majority of the cells are spindle-shaped at first, but as the stage advances on, these cells become larger and more rounded, become foam cells and collagen fibres start to proliferate and form granulomatous lesions, which are characterised by dense collagen fibres surrounding typical foam cells.⁴ Amirhakimi et al. discovered lymphocytes and plasma cells in areas of early fibrosis.⁵ In the most advanced stage, these collagen fibres can be hyalinised. The results of the histochemical stains have varied, depending on whether frozen or paraffin sections were utilised. The early-stage intracytoplasmic PAS-positive material is resistant to extraction with hot pyridine, hyaluronidase and diastase digestion. These materials, which are positive for colloidal iron and alcian blue staining, are assumed to represent non-sulfated acid mucopolysachharides and glycopeptides. A weak toluidine blue reaction (pH 4.1) demonstrates metachromasia. These materials could also be positive with Baker’s reaction for phospholipid, sudan IV, sudan black B and oil red O, thereby suggesting that thay may be ceramides.^4,5 Semi-curvilinear inclusions, commonly referred to as Farber bodies, zebra bodies or banana bodies can be seen using electron microscopy in lung histiocytes, hepatocytes, endothelial cells and Kupffer cells.⁶ These bodies are curvilinear bodies within the cytoplasm of fibroblasts and occasionally of endothelial cells. They are also found within phagosomes of histiocytes at various stages of degradation.⁷

In our case, the girl exhibited classic symptoms like subcutaneous nodules, arthritis along with corneal dystrophy, features of neuroregression, myoclonic jerks and DDH. She also experienced stridor but without associated hoarseness in her voice, and therefore, the typical triad was not present. DDH is described commonly with cerebral palsy patients but it has not described with FD previously in the literature.⁸ Cherry red spots in the macula were absent in this case. Other disorders like stiff skin syndrome, juvenile hyaline fibromatosis and multicentric reticulohistiocytosis that may also present with subcutaneous nodules and joint contractures must be excluded.

There is currently no specific enzyme replacement therapy for FD; instead, symptomatic and supportive treatment are the mainstays of care. Early diagnosis and treatment are crucial. Before the beginning of neurological symptoms, haematopoietic stem cell transplantation may be beneficial.⁹