A Heterozygous Mutation in the GJA1 Gene Causes Severe Erythrokeratodermia Variabilis et Progressiva in a Chinese Family

0
0
0

A Heterozygous Mutation in the GJA1 Gene Causes Severe Erythrokeratodermia Variabilis et Progressiva in a Chinese Family

Rare genetic skin disorders can be frustratingly hard to diagnose—especially when symptoms overlap with other conditions. For one Chinese family, a decades-long journey to understand their progressive skin disease led to a critical discovery: a mutation in the GJA1 gene is responsible for their severe form of erythrokeratodermia variabilis et progressiva (EKVP), a rare inherited skin disorder.

Researchers from Anhui Medical University and collaborating institutions recently published these findings in the Chinese Medical Journal, shedding light on how genetic testing can solve even the most complex diagnostic puzzles.

The Family’s Journey with EKVP

The study focused on a 27-year-old man (the “proband”) who first developed red, scaly patches on his palms and soles at just 1 month old. As he grew, the lesions spread to his arms, legs, elbows, thighs, and hips—becoming thick, crusted, and slow to heal. Over the years, he was misdiagnosed multiple times: generalized verrucous epidermal nevus, classic erythrokeratodermia variabilis (EKV), and autosomal dominant congenital ichthyosiform erythroderma. Treatments like cod-liver oil, urea cream, and vitamin E cream did nothing to ease his symptoms.

His father had nearly identical skin findings, confirming the condition was inherited in an autosomal dominant pattern (passed from one parent, with a 50% chance of affecting each child). Neither the proband nor his father had issues with their nails, hair, mouth, or other organs—common in some related disorders but absent here.

Clinical and Lab Findings

A skin biopsy revealed key clues: hyperkeratosis (a thickened outer skin layer), granular-layer hypertrophy (enlarged middle skin layer), and acanthosis (thickened epidermis). Immune cells (lymphocytes) clustered around superficial blood vessels, a sign of mild inflammation. Blood, urine, and stool tests were normal, as were heart and lung exams.

Genetic Testing Unlocks the Diagnosis

Initially, doctors tested for mutations in KRT1 and KRT10—genes linked to other ichthyotic (scaly) skin disorders—but found no abnormalities. To dig deeper, they used next-generation sequencing to analyze 541 genes associated with genodermatoses (genetic skin diseases).

The result? A heterozygous missense mutation in the GJA1 gene: c.131C→T (p.A44V). This mutation changes an amino acid (alanine to valine) at a highly conserved position in the protein, meaning it’s critical for function.

Sanger sequencing (a gold-standard method for validating mutations) confirmed the same change in the proband’s skin tissue and his father’s blood. Unaffected family members and 200 healthy, ethnically matched controls had no trace of the mutation. Software tools classified the mutation as “pathogenic,” and immunohistochemistry showed strong expression of connexin 43 (Cx43)—the protein made by GJA1—in the patient’s epidermis, compared to weak or negative expression in healthy skin.

What GJA1 and Cx43 Do

GJA1 encodes connexin 43, a gap junction protein that lets cells share nutrients and signals. It’s found in nearly every organ, including the skin. Mutations in GJA1 (and related genes like GJB3 and GJB4) are known to cause EKVP, but most previous cases were sporadic (not inherited). This family’s case is unique: it’s the first reported familial instance of GJA1-related EKVP with such severe symptoms.

Why This Matters

EKVP is defined by transient red patches, scaling, and palmoplantar keratoderma (thickened palms/soles). For this family, the GJA1 mutation led to widespread, progressive disease—worse than most sporadic cases. The findings confirm that GJA1 mutations can cause inherited EKVP and highlight the need for genetic testing in rare skin disorders.

About the Researchers

The study was led by Bi-Rong Guo (Department of Dermatology, Third Affiliated Hospital of Anhui Medical University/First People’s Hospital of Hefei) and Hai-Bin Cai (Department of Dermatology, People’s Hospital of Pudong New Area). Collaborators included teams from the Institute of Dermatology (Chinese Academy of Medical Sciences and Peking Union Medical College) and Xinhua Hospital (Shanghai Jiaotong University School of Medicine). Funding came from the National Natural Science Foundation of China (81301352), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20161417), and Anhui Provincial Hefei City Program (hwk2017yb008).

References

  1. van Steensel MA, Oranje AP, van der Schroeff JG, Wagner A, van Geel M. The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am J Med Genet A 2009;149A:657–661.
  2. van Steensel M. Does progressive symmetric erythrokeratoderma exist? Br J Dermatol 2004;150:1043–1045.
  3. Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, et al. Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia. J Invest Dermatol 2015;135:1540–1547.
  4. Ishida-Yamamoto A. Erythrokeratodermia variabilis et progressiva. J Dermatol 2016;43:280–285.
  5. De Bock M, Kerrebrouck M, Wang N, Leybaert L. Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system? Front Pharmacol 2013;4:120.

doi.org/10.1097/CM9.0000000000000011

Was this helpful?

0 / 0