Neonatal ichthyosis–sclerosing cholangitis syndrome

Overview

Neonatal ichthyosis–sclerosing cholangitis (NISCH) syndrome is a rare autosomal recessive genetic disorder that primarily affects the skin and liver. It is characterized by the combination of congenital ichthyosis (a skin disorder leading to dry, scaly skin) and sclerosing cholangitis (a chronic liver disease involving inflammation and scarring of the bile ducts). First described in a few isolated cases, NISCH syndrome is recognized as a multisystem disorder presenting in the neonatal period or early infancy.

Children affected by NISCH syndrome typically exhibit skin abnormalities from birth, followed by progressive liver dysfunction, which can lead to serious complications if not identified and managed promptly. Because of its rarity, NISCH syndrome may often be misdiagnosed or confused with other congenital ichthyosis or cholestatic liver disorders.

Causes

Neonatal ichthyosis–sclerosing cholangitis syndrome is caused by mutations in the CLDN1 gene, which encodes the protein claudin-1. Claudin-1 is an essential component of tight junctions in epithelial cells, which are structures that help maintain the integrity of barriers such as the skin and bile ducts.

Mutations in the CLDN1 gene disrupt tight junction formation, resulting in increased permeability and dysfunction of epithelial barriers. This leads to the characteristic skin abnormalities seen in ichthyosis and contributes to bile duct injury and fibrosis, eventually resulting in sclerosing cholangitis.

The disorder follows an autosomal recessive inheritance pattern. This means a child must inherit two mutated copies of the gene—one from each parent—to develop the condition. Parents are typically unaffected carriers.

Symptoms

The hallmark features of NISCH syndrome involve the skin and liver, although other organs may be mildly affected. Symptoms usually appear at or shortly after birth.

Dermatologic Features

• Congenital ichthyosis: Generalized dry, scaly, thickened skin present from birth

• Erythema: Reddening of the skin may be present in the neonatal period

• Scaling may vary in severity, sometimes resembling lamellar ichthyosis or other types of congenital ichthyosis

Hepatic Features

• Sclerosing cholangitis: Chronic inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts

• Cholestasis: Impaired bile flow, leading to jaundice, pale stools, and dark urine

• Hepatomegaly: Enlarged liver due to bile accumulation and inflammation

• Progressive liver dysfunction: Can lead to liver fibrosis, portal hypertension, and liver failure if unmanaged

Other Possible Features

• Failure to thrive or poor weight gain due to chronic illness

• Pruritus (intense itching) due to bile salt accumulation

• Vitamin deficiencies (especially fat-soluble vitamins A, D, E, and K)

• Hypoproteinemia and coagulopathy in advanced stages

Diagnosis

The diagnosis of NISCH syndrome is based on a combination of clinical features, laboratory findings, imaging studies, histopathology, and genetic testing. Given its rarity, diagnosis often requires exclusion of more common disorders and referral to a specialized center.

• Clinical examination: Observation of congenital ichthyosis and hepatobiliary symptoms

• Liver function tests: Elevated liver enzymes (e.g., ALT, AST), bilirubin, and alkaline phosphatase indicating cholestasis

• Abdominal ultrasound or MRCP: May show bile duct abnormalities or fibrosis

• Skin biopsy: Shows structural abnormalities consistent with ichthyosis and loss of tight junction integrity

• Liver biopsy: Confirms sclerosing cholangitis and assesses fibrosis or cirrhosis

• Genetic testing: Definitive diagnosis is made by identifying biallelic mutations in the CLDN1 gene

Treatment

There is currently no cure for NISCH syndrome, and treatment is primarily supportive and symptomatic. Early and coordinated multidisciplinary care can help manage symptoms and delay progression of liver disease.

Dermatologic Management

• Emollients and moisturizers: To hydrate and protect the skin

• Keratolytic agents: Such as urea or lactic acid to reduce scaling

• Regular skin care routines to prevent infections and maintain barrier integrity

Hepatic Management

• Ursodeoxycholic acid (UDCA): To improve bile flow and reduce cholestasis

• Fat-soluble vitamin supplementation: Especially vitamins A, D, E, and K

• Antipruritic agents: Such as antihistamines or cholestyramine for itch relief

• Nutritional support: High-calorie diet and specialized formulas for infants with malabsorption

• Liver transplantation: May be necessary in cases of advanced liver disease or liver failure

Prognosis

The prognosis for individuals with NISCH syndrome varies depending on the severity of liver involvement. Skin symptoms, though persistent, can often be managed with supportive care. However, progressive liver disease poses the most significant long-term risk.

Without proper intervention, chronic cholangitis can lead to biliary cirrhosis, liver failure, and potentially life-threatening complications. In severe cases, liver transplantation may offer a chance for long-term survival and improved quality of life. Early diagnosis and proactive management of nutritional and hepatic issues are key to improving outcomes.

Due to the rarity of the condition, long-term data is limited, and continued research and case documentation are essential to enhance understanding and improve therapeutic approaches for NISCH syndrome.