Generalised granuloma annulare in a child with Alagille syndrome with a novel mutation

Dear Editor,

Alagille syndrome (ALGS)/Alagille-Watson syndrome is a rare and autosomal dominant disorder with an estimated frequency of 1: 30,000–1:50,000. It is caused by mutations in the JAG1 (90%) or NOTCH2 (10%) genes.¹ The paucity of bile ducts is the characteristic feature, with almost all cases manifesting cholestatic liver disease.² Here in we report a case of ALGS with a novel mutation, who presented with generalised granuloma annulare (GA).

A 2-year-old male child born of a non-consanguineous marriage presented with generalised, severe pruritus since 6 months of age. It was insidious in onset, gradually progressive, and not relieved with antihistamines. Additionally, he had a history of gradual development of skin-coloured, raised, annular lesions over the trunk and both lower limbs over the last 4 months. There was a history of yellowish discolouration of the conjunctiva, pale stools, and dark coloured urine since day 4 of life. Developmental milestones were delayed. No other family member was affected similarly.

The child was irritable. His height was 62 cm (-8.71 SDS) and weight was 7 kg (-4.98 SDS). Mild pallor and icterus were present along with firm, non-tender hepatomegaly extending 2 cm below the right costal margin. The rest of the systemic examination was normal. Cutaneous examination revealed skin-coloured discrete papules along with annular plaques, interspersed with a few satellite lesions, over the bilateral lower limbs and trunk [Figure 1a and 1b]. Mucous membranes, palms, soles, hair, nails, and teeth were normal. 

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Figure 1a:

Well-defined annular plaques with raised margins present over the back with few satellite lesions.

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Figure 1b:

Well-defined annular plaques with raised margins present over the abdomen with few satellite lesions.

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Upon laboratory work up, liver function tests were impaired with conjugated hyperbilirubinemia, raised serum alanine transaminase [ALT] (106 U/L), aspartate amino transferase [AST] (95 U/L), alkaline phosphatase (704 U/L), γ-glutamyl transferase (326 U/L), bile acids (42.9 µmol/L), and low serum globulins (2.1 g/dL) and total protein (5.7 g/dL). Haemoglobin was 10.2 g%, platelets were 4,25,000 lakhs/mm,³ and the total leukocyte count was 7,500 cells/mm.³ The total cholesterol (138 mg/dL), triglycerides (154 mg/dL), and high-density lipoprotein (27 mg/dL) were deranged. A Tc-99m mebrofennin hepatobiliary scan showed an enlarged liver with impaired hepatocyte function. Liver biopsy revealed paucity of intrahepatic bile ducts. A novel de novo pathogenic, heterozygous 5’ splice site variation in intron 19 of the JAG1 gene, that affected the invariant GT donor splice site of exon 19 (c.2372+1G>C) was found on next-generation sequencing, suggestive of ALGS. It was confirmed by Sanger validation and was predicted to be damaging by MutationTaster2. Both parents were screened for the same gene and were not carriers. A skin biopsy revealed unremarkable epidermis with dermis showing a perivascular and interstitial infiltrate comprising of histiocytes, multinucleated giant cells with altered collagen suggestive of interstitial GA [Figure 2a and 2b]. Based on the above, the child was diagnosed with ALGS and interstitial-type GA.

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Figure 2a:

Histopathology section showing an unremarkable epidermis and dermis showing a perivascular and interstitial infiltrate comprising of histiocytes (Black arrows), multinucleated giant cells (Blue arrow) with altered collagen (Red arrows) suggestive of interstitial granuloma annulare (Haematoxylin and eosin, 100x)

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Figure 2b:

Histopathology section showing an unremarkable epidermis and dermis showing a perivascular and interstitial infiltrate comprising of histiocytes (Black arrows), with altered collagen (Red arrows) suggestive of interstitial granuloma annulare (Haematoxylin and eosin, 400x)

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He was treated with desonide (0.05%) cream twice daily for 2 weeks, followed by tacrolimus (0.03%) ointment twice daily for 3 months, but showed recurrence after stopping. He was also prescribed rifampicin, ursodeoxycholic acid, cholestyramine, fat-soluble vitamins (A, D3, E, K), and medium chain triglyceride oil.

ALGS (OMIM#118450) is a rare, autosomal dominant arterio-hepatic dysplasia caused by heterozygous mutations in JAG1 (OMIM*601920) or NOTCH2 (20p12.1). JAG1 (26 exons) encodes Jagged-1, a Notch receptor ligand, while the NOTCH2 (34 exons) protein mediates signalling. Mutations (nonsense, frameshift, splice-site, missense) occur de novo in ∼⅔ of cases, with germline mosaicism contributing to a slightly increased recurrence risk. The syndrome shows high penetrance with variable expressivity.

There are five main clinical abnormalities in the syndrome: cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype. Affected children usually present before 6 months with neonatal jaundice or cardiac murmur, followed by poor growth. Characteristic facies include a broad forehead, pointed chin, deep-set eyes, and an elongated nose with a bulbous tip.⁴ Icterus, intense pruritus, and xanthomas are the most common cutaneous features in ALGS, indicating underlying metabolic abnormalities.

A single report of granuloma annulare with ALGS has been described earlier.⁴ ALGS is associated with sarcoidosis and giant cell granulomas. JAG1 mutations likely alter T-cell development, as Notch-1, highly expressed in the thymus, regulates CD4⁺ T-cell differentiation. Disrupted Jagged1/Notch interactions may impair the T cell receptor (TCR)γδ and TCRαβ T-cell populations leading to a Th1-mediated granulomatous response.^5-7 The possible underlying mechanisms for other dermatological manifestations in ALGS have been reviewed in Table 1, and cutaneous findings in ALGS are reviewed in Supplementary Table 1.

Hepatic transplant is a preferred surgical treatment, often resolving xanthomas and pruritus. The 20-year survival is 80% without and 60% with transplantation.²

This case is being highlighted for unusual association of ALGS with generalised interstitial GA. Our patient also had a novel de-novo mutation. Dermatologists must be aware of the association of this rare condition.