Gaucher disease with severe congenital ichthyosiform erythroderma in two siblings

Dear Editor,

Gaucher disease (GD) is a rare, autosomal recessive, lysosomal disorder caused by the accumulation of glucosylceramides, resulting in diverse clinical presentations. We report two young Indian siblings with severe congenital ichthyosis and systemic complications related to type 2 GD.

A three-year-old child (patient 1) presented with peeling skin for 1-month of age, along with a history of seizures, fever, loose stools, decreased feeding and activity, frequent hospitalisations due to recurrent infections, multiple blood transfusions and failure to thrive. There was no history of collodion membrane at birth and consanguinity in the parents. The developmental milestones were delayed.

On general examination, the child had pallor, coarse facies, microcephaly, stunting and severe malnutrition. Cutaneous examination revealed ichthyosiform scaling, generalised desquamation and fissuring of skin over the whole body. Nails were thickened and dystrophic. Oral and genital mucosae were normal. Clinical examination suggested congenital ichthyosiform erythroderma (CIE) [Figures 1a and 1b].

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Figure 1a:

Patient 1, Generalised ichthyosis with desquamation and fissuring and arthrogryposis.

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Figure 1b:

Ichthyosiform, yellow-brown coarse scales with desquamation of skin over the back.

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Ophthalmological examination revealed ectropion and bilateral corneal opacities [Figure 1c]. Musculoskeletal examination revealed arthrogryposis, hypotonia and spasticity. The remaining systemic examination was normal. Hepatosplenomegaly was absent. The patient had reduced haemoglobin (4.8 g/dl) with normal liver/kidney function tests. Magnetic resonance imaging (MRI) of the brain showed subacute haemorrhaging in bilateral ventricles along with pontocerebellar hypoplasia. Whole abdomen ultrasonography was unremarkable. Histopathological examination of the skin was consistent with CIE [Figure 2a, 2b]. Whole genomic sequencing of the patient’s blood sample depicted heterozygous missense variation (c.1448T>C) in exon 10 of the glucocerebrosidase (GBA) gene that led to substitution from leucine to proline at codon 483 (p.Leu483Pro), likely pathogenic variant suggestive of GD.

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Figure 1c:

Ectropion and visible corneal opacities in bilateral eyes.

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Figure 2a:

Histopathological examination (Haematoxylin & eosin, 100×) shows hyperkeratosis and irregular acanthosis of the epidermis. Dermis shows mild perivascular lymphocytic infiltrate with melanin incontinence.

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Figure 2b:

Histopathological examination (Haematoxylin & eosin, 400×) shows lamellar hyperkeratosis with parakeratosis and exocytosis of neutrophils and lymphocytes.

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The younger sibling of the above patient (patient 2), a three-month-old female, presented with similar cutaneous and systemic complaints since 1.5 months of age along with fever, cough, feeding difficulties and delayed developmental milestones. On general examination, pallor, microcephaly and severe stunting were evident. Cutaneous findings were similar to the elder child [Figures 3a and 3b]. Abdominal palpation revealed hepatomegaly 3 cm below and splenomegaly 2 cm below the respective costal margins. Musculoskeletal examination revealed reduced power (MRC grading 3/5) in bilateral upper and lower limbs with hypotonia. The rest of the systemic examination was normal. Investigations revealed reduced haemoglobin (6.8 g/dl), raised total leucocyte count (26,000/mm³) and hypoproteinaemia. Other investigations were normal. The skin biopsy findings were consistent with CIE. The younger child expired after a few days due to aspiration pneumonia and the older sibling was started on treatment with systemic antibiotics, topical emollients and antibiotic ointments. Parents were advised genetic counselling for the disease.

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Figure 3a:

Patient 2 – Generalised lamellar ichthyosis with fissuring of skin in folds, flexion contractures of upper and lower limbs, arthrogryposis and palmoplantar keratoderma.

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Figure 3b:

Patient 2 – ichthyotic scaling, desquamation of skin over lower limbs.

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GD is the most common lysosomal storage disorder resulting from deficiency of the GBA enzyme due to mutation of the GBA1 gene, located on chromosome 1 (1q21).¹ There are three subsets of the disease. Type 1 GD is the non-neuronopathic form, while type 2 GD and type 3 GD are the neuronopathic forms.² The phenotypes of GD are summarised in Table 1. Type 2 GD (acute, infantile form) is a rare sub-type of GD. It usually appears within two years of age, progresses rapidly, and death may occur by 3–4 years of age.³ The perinatal lethal (PNL) form of type 2 GD Table 1 is associated with onset in-utero, extending to 3 months of age and may lead to death within 3 months. Our 2^nd patient presented with similar findings. The non-perinatal lethal form of type 2 GD presents relatively late, till the age of two years with visceral and/or neurologic symptoms and microscopic skin changes (immature lamellar membranes), similar to our first patient.⁴ The individuals homozygous for GBA1 pathogenic variant c.1448T>C (p.Leu483Pro) (earlier known as L444P) present with severe disease and often with neurologic complications such as earlier onset and worsening of Parkinson’s disease.² In the Indian spectrum, c.1448T>C is reportedly the most recurrent mutation, followed by D409H in patients of GD.⁵ The homozygosity for the complex allele L444P alongside E326 K mutation (c.1093G>A, exon 8) or heterozygosity for another allele such as P182L can be associated with severe PNL forms.⁶

The PNL phenotypic type of GD is sporadic and has only been mentioned in a single case report by Aggarwal et al. from India, who found a heterozygous mutation of the RecNcil allele (missense mutation of three genes, namely, L444P, A456P and V460V) in both the parents of the foetus with gross intrauterine anomalies.⁷

This case report emphasises that severe ichthyosis in association with systemic complications may indicate GD. Genetic testing helps in the identification of this metabolic disorder and clears up the path for appropriate genetic counselling for future pregnancies.