About
Browse articles
For contributors
All issues > Volume 68(11); 2025
Neonatal ichthyosis-sclerosing cholangitis syndrome caused by a novel CLDN1 mutation: a case report and literature review
-
Upasana Ghosh, MD, DM1
, Ankit Agrawal, MD, DM1, Varunvenkat M. Srinivasan, MD, DM2, Rani Manisha, MD, DM2, Umesh Shukla, MD1, Vikas Jain, MD, DM1, Mayank Nilay, MD, DM2, Harish Kumar, MD3
- Corresponding author: Mayank Nilay, MD. Department of Medical Genetics, Post Graduate Institute of Child Health, Noida, Uttar Pradesh 201303, India Email: mnilay21@gmail.com
- Received April 19, 2025 Revised July 8, 2025 Accepted July 9, 2025
- Abstract
-
Neonatal ichthyosis-sclerosing cholangitis syndrome (NISCH) is an autosomal recessive disorder characterized by cholestasis, generalized ichthyosis, alopecia, and dental anomalies. As this is a rare syndrome, here we present a case caused by a novel mutation followed by a literature review of all published cases. This retrospective review includes all original articles on the clinical profiles of all 37 cases published through December 2024 using a PubMed search. The patient was a 2-month-old boy who presented with cholestasis, sparse hair, and generalized ichthyosis. Whole-exome sequencing revealed a novel pathogenic variation in exon 1 of the CLDN1 gene: (NM_021101.5) c.36dupT (p.Leu13SerfsTer56). The patient was symptomatically managed, and his condition improved. Among the 37 reported cases, the median age at diagnosis was 60 months (range, 1–636 months). Patients of Moroccan ethnicity were most commonly affected, and c.200_201delTT was the most common mutation. Among the clinical features, ichthyosis was universal (37 of 37 [100%]), followed by jaundice in 70.2% (26 of 37), pruritus in 38.2% (13 of 34), hepatomegaly in 43.3% (13 of 30), and splenomegaly in 23.8% (5 of 21) of patients. Portal hypertension (7 of 35 [20%]) and mental retardation (3 of 21 [14.2%]) were rare. The disease phenotype varied from no liver involvement or transient neonatal cholestasis to end-stage liver disease. Progressive liver disease was reported in 8 patients, five of whom underwent liver transplantation. NISCH is a rare syndrome with variable phenotypes ranging from no liver involvement and transient neonatal cholestasis to advanced liver disease requiring liver transplantation. Therefore, a multidisciplinary approach with close follow-up is required.
- Introduction
- Introduction
Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome, also known as ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC), is a rare autosomal recessive disorder characterized by a combination of ichthyosis, sclerosing cholangitis, and dental and hair changes. The syndrome is caused by pathogenic variations in the CLDN1 gene (chromosome 3q27-q28) [1]. NISCH syndrome was first described in patients of Moroccan ancestry by Baala et al. in 2002 [2]. It has a characteristic presentation at birth with generalized ichthyosis and neonatal cholestasis. Liver involvement varies, ranging from transient neonatal cholestasis to end-stage liver disease. Its hallmark dermatological manifestations include ichthyosis, hair changes such as alopecia and hypotrichosis, and dental anomalies such as enamel hypoplasia. Other differential diagnoses of neonatal cholestasis with ichthyosis include arthrogryposis-renal dysfunction-cholestasis syndrome, MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratoderma) syndrome. As it is a rare syndrome caused by pathogenic variations in a single gene (CLDN1), increased knowledge of NISCH syndrome will not only expedite early diagnosis by targeted genetic analysis but also avoid misdiagnosis. Here we report a novel genetic mutation and review 37 genetically confirmed cases published to date. This review highlights the variable disease phenotypes and multisystem involvement and underscores the importance of early genetic diagnosis for the multidisciplinary management of NISCH syndrome
- Methods
- Methods
We searched for original articles, case series, and case reports describing clinical profiles of NISCH syndrome on PubMed using the keywords “NISCH syndrome” or “ILVASC syndrome” or “Ichthyosis” AND “Sclerosing cholangitis” for articles published between January 2002 and December 2024. The relevant literature was retrieved and independently assessed for eligibility by 2 authors and then reviewed by the remaining authors. We identified 32 articles, of which 21 included clinical descriptions of 37 genetically confirmed cases. We summarized the clinical findings, including age at presentation, hepatic and dermatological involvement, affected ethnicities and their mutations, diagnostic work-up findings, and patient outcomes. Written informed consent was taken from the parents for anonymous publication for the patient’s clinical details and photographs of the case report. Here we present a case report, followed by a detailed review of NISCH syndrome including all cases published through December 2024.
- Case report
- Case report
A 2-month-old boy born to nonconsanguineous parents (term delivery, no perinatal complications) presented with jaundice, dark urine, pigmented stools, and generalized ichthyosis since the first week of life. He weighed 4.3 kg (-1.92 standard deviation [SD]) and measured 61 cm (-1.21 SD). A physical examination revealed icterus, generalized ichthyosis, and sparse hair and eyebrows (Fig. 1A). An abdominal examination revealed soft hepatomegaly (palpable 4 cm below the right costal margin) and splenomegaly (2 cm). Laboratory investigations revealed conjugated hyperbilirubinemia with preserved synthetic liver function (Fig. 2). The hemogram was normal. Abdominal ultrasonography revealed a good-sized gallbladder (2.5 cm) and a normal common bile duct (1.6 mm). An ophthalmological examination revealed no evidence of uveal synechia or cataracts. We suspected NISCH syndrome based on the presence of neonatal cholestasis with generalized ichthyosis and sparse hair. Whole-exome sequencing (WES) revealed a homozygous variant in exon 1 of the CLDN1 gene: (NM_021101.5) c.36dupT (p.Leu13SerfsTer56). This variant was classified as likely pathogenic based on American College of Medical Genetics and Genomics criteria. Sanger sequencing revealed that both parents were heterozygous asymptomatic carriers of the variant (Fig. 3).The infant was treated with vitamins D (800 IU/day) and E (200 IU/day), ursodeoxycholic acid (20 mg/kg/day), and multivitamins. Medium-chain triglyceride-based oil was added for caloric supplementation. Urea-based emollient creams were used to treat the ichthyosis. By the 7-month follow-up, the ichthyosis and jaundice had resolved completely, although mild pruritus persisted (Fig. 1B).
- Discussion
- Discussion
Our patient presented with cholestasis, hepatosplenomegaly, generalized ichthyosis, sparse hair, and elevated transaminase levels. WES identified a novel variant in the CLDN1 gene (c.36dupT, p. Leu13SerfsTer56, exon 1) that resulted in a premature termination codon, leading to a truncated protein product. This clinical picture was similar to the 37 globally reported cases among patients of various ethnicities (Table 1) [1-21]. In the literature review, the median age at diagnosis was 60 months (range, 1–636 months), and consanguinity was reported in 56.7% of cases (21 of 37). At presentation, ichthyosis was universal (37 of 37 [100%]), followed by jaundice in 70.2% (26 of 37), pruritus in 38.2% (13 of 34), hepatomegaly in 43.3% (13 of 30), and splenomegaly in 23.8% (5 of 21) of the patients (Table 1). Associated features included hypotrichosis/alopecia (30 of 36 [83.3%]), oligodontia/hypodontia (11 of 28 [39.3%]), enamel hypoplasia (16 of 27 [59.2%]), and uveal synechiae (1 patient). Portal hypertension (7 of 35 [20%]) and mental retardation (3 of 21 [14.2%]) were rare. A peripheral blood smear showed vacuolated eosinophils in 30% (3 of 10) of patients. All patients were homozygous for pathogenic variants of the CLDN1 gene, the most common variant was exon 1, c.200_201delTT (16 of 37 [43.2%]), followed by c.242G>A (9 of 37 [24.3%]), and the parents were typically asymptomatic.Percutaneous cholangiography performed in 5 patients revealed sclerosing cholangitis in 3 (at 5–6 years of age) and hypoplastic bile ducts in 2 (age unknown). Magnetic resonance cholangiopancreatography was performed in one patient, which was normal [2,4,9]. A liver biopsy performed in 14 patients revealed fibrosis and bile duct proliferation in 50% (7 of 14) as well as ductopenia in 21.4% (3 of 14) [1,2,4,5,8,9,12,14,18,21]. On liver biopsy, the typical ‘‘onion-skin’’ appearance of periductal fibrosis was not seen as expected considering the age of the patients [22]. Ductopenia, a well-documented histopathological feature of sclerosing cholangitis, is most commonly observed in stage 3 of the disease according to the Ludwig classification [23]. Nagtzaam et al. [4] reported 2 cases of bile duct paucity without any significant fibrosis, suggesting that it may be a primary phenomenon due to abnormal bile duct development rather than a sequela. On the contrary, Paganelli et al. [5] showed ductopenia in the explant liver of a patient at 1 year of age that was not present at initial presentation. Thus, long-term follow-up and explant liver biopsy may aid our understanding of the biliary pathology in NISCH syndrome. In our patient, a liver biopsy was deferred since the liver function tests showed improvement. Another difficulty associated with this condition is the close resemblance of its clinical features to those of biliary atresia, which may lead to a misdiagnosis. Four cases in the literature were initially misdiagnosed as biliary atresia; 3 of these patients underwent the Kasai procedure within the first 2 months of life [5,16,18,21]. These patients subsequently progressed to chronic liver disease: 3 of 4 underwent liver transplantation at the ages of 1 and 8 years (age unavailable for the third) [5,16,18,21]. This underscores the importance of diagnostic accuracy to avoid the Kasai procedure.Ichthyosis, a universal finding secondary to defects in the epidermal barrier, cannot be corrected by liver transplantation [5,9,16,18]. In contrast, Baala et al. [2] reported the case of a patient in whom complete regression of ichthyosis and alopecia was noted post-transplant while on immunosuppression with tacrolimus, a finding that remains unexplained. A receding frontal hairline, alopecia, hypotrichosis, and curly hair are other characteristic dermatological findings (Table 1).The CLDN1 gene encodes claudin-1, a key protein in tight junctions found in keratinocytes, hepatocytes, and cholangiocytes [2,11,24,25]. Defective tight junctions result in loss of the epidermal barrier function. In the liver, paracellular leakage of bile from the biliary canaliculi leads to pericholangiocellular inflammation, fibrosis, and bile duct obliteration, resulting in sclerosing cholangitis. Furthermore, claudin-1 is also expressed in extrahepatic bile ducts, and tight-junction dysfunction has been associated with abnormal bile duct development [11,24,25]. Claudin-1 is also expressed in the tight junctions of developing enamel-secreting cells (ameloblasts) and hair follicles, which explains the enamel defects and abnormal hair phenotype present in these patients. The pathogenesis of pruritus in NISCH syndrome is likely related to epithelial barrier dysfunction (bile acid levels were normal in one case report) [5,9,19].Differential diagnoses for infants presenting with generalized ichthyosis and cholestasis include arthrogryposis, renal dysfunction, cholestasis syndrome; MEDNIK syndrome; and type 2 Gaucher disease (Table 2). In our case, WES performed with full coverage of the above genes did not reveal any significant single nucleotide variants or large copy number variations in the genes associated with the other differential diagnoses.The natural history and prognosis of NISCH syndrome remain unclear; perhaps, it is underdiagnosed, as only 37 cases have been reported to date. However, its prevalence appears to vary among ethnicities. A literature search showed 12 significant disease-causing variations (missense, n=3; nonsense, n=9) in the CLDN1 gene that included exon 1—c.200_201delTT, the Moroccan founder mutation in 40.5% (15 of 37), followed by c.242G>A variant in 24.3% (9 of 37), c.181C>T, p.Gln61X in the Turkish population (n=3), and c.578C>A, p.Tyr159Ter in the Kurdish (Iranian) population (n=2) and a homozygous deletion in the nucleotide of exon 2, c.358delG, p.Val120fs in the Swiss population (n=1). The remaining variants are shown in Table 1. All patients were homozygous for pathogenic variants. Exon 1 of the CLDN1 gene seems to be a hotspot for mutations, and targeted cost-effective approaches such as Sanger sequencing can be performed if NISCH syndrome is suspected. Ours is the fourth case reported of a patient of Indian ethnicity; all 3 patients with different mutations described previously, had transient neonatal cholestasis with a good prognosis [12,17,19]. The Swiss, Swiss-Turkish, and Turkish mutations reportedly have a better prognosis (regression of cholestasis, n=2; no liver involvement, n=2), in contrast to the Moroccan mutation, which is reportedly associated with variable outcomes ranging from no liver involvement to severe liver disease, making the prognosis unpredictable. Phenotypic variation within the same family is well documented, even within the same mutation, ranging from no liver involvement to advanced liver disease [2,3,4,5,6,18]. The presence of phenotypic variability in the same family complicates the genotype–phenotype relationship. Our patient's family history was noncontributory (Fig. 3A). In the literature review, followup data were available for 34 patients; 8 of them (23.5%) had isolated skin involvement without any liver involvement. Among those with liver disease, bilirubin had normalized in 52.9% (18 of 34) by age 1–29 months. Notably, in 6 studies, 8 patients progressed to chronic liver disease, of whom 5 underwent liver transplantation [2,4,5,16,18,21]. This highlights that NISCH syndrome carries significant morbidity and requires monitoring for the progression of liver disease. It is difficult to determine whether transient neonatal cholestasis responds to ursodeoxycholic acid or it is the natural history of the disease.The management of NISCH syndrome primarily focuses on symptom management, i.e., the treatment of cholestasis with ursodeoxycholic acid and fat-soluble vitamin supplementation, use of moisturizers and emollients, good hydration for the ichthyosis, and dental coverings with crowns or resins for enamel dysplasia. In severe cases, liver transplantation may be necessary to treat the end-stage liver disease. We recommend 3–6 monthly follow-ups with growth monitoring; skin, hair, and teeth examinations; monitoring of liver and spleen size by ultrasonography; liver function tests; regular cognitive assessments to identify intellectual delays; and ophthalmological examinations for uveal synechiae. Liver stiffness can be measured by using transient elastography to identify portal hypertension. Parental counseling regarding the natural history of the disease, especially regarding complications related to liver disease, is necessary. Genetic counseling and prenatal testing for families with a history of NISCH syndrome (25% risk of recurrence) enables its early diagnosis.In summary, here we presented a case of NISCH syndrome with transient cholestasis and ichthyosis and highlighted a novel mutation. NISCH syndrome poses diagnostic and therapeutic challenges owing to its clinical heterogeneity and rarity. The specific association of ichthyosis, hypotrichosis, and cholestasis in the context of consanguinity is a key element in guiding the diagnosis. Moreover, its management requires a multidisciplinary approach involving dermatologists, dentists, hepatologists, and geneticists. It is important to note that liver transplantation does not resolve extrahepatic manifestations and should be reserved for patients with end-stage liver disease. To date, most of the literature on NISCH syndrome comprises short case reports and case series; thus, long-term follow-up studies are required to better elucidate the natural history and genetics of this rare condition.
- Footnotes
-
Conflicts of interest No potential conflict of interest relevant to this article was reported.
Funding This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author contribution Conceptualization: MN; Methodology: UG, AA, VMS, RM; Data curation: UG, AA, VMS, RM; Writing-Original draft preparation: UG, AA, VMS, RM; Visualization: UG, AA, VMS, RM, US, VJ, HK, and MN; Investigation: UG, AA, VMS, RM, US, VJ, HK, and MN; Formal analysis: UG, AA, VMS, RM, US, VJ, HK, MN; Supervision: US, VJ, MN; Validation: US, VJ, MN; Writing-Reviewing and Editing: US, VJ, MN
-
Fig. 1.
(A) Clinical images showing ichthyosis on the trunk and the scalp at the age of 2 months. (B) Clinical images taken at 7 months of age show the persistence of alopecia, however, the ichthyosis on the scalp and the back had resolved.
Fig. 2.
Graphical representation of serial liver function tests of the patient. (A) Trend of total and direct serum bilirubin (mg/dL), albumin (g/L), and INR. (B) Trend of AST (U/L), ALT (U/L), and GGT (U/ L). AST, aspartate amino transferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; INR, international normalized ratio.
Fig. 3.
(A) Pedigree chart depicting the affected child and the parents' carrier status. (B) Sanger chromatogram showing the novel mutation “c.36dupT” in the parents and child.
Table 1.
CLDN1 gene variants and phenotypes of cases reported worldwide to date
| Variable | Baala et al. [2] & Hadj-Rabia et al. [3] | Feldmeyer et al. [1] | Nagtzaam et al. [4] | Paganelli et al. [5] & Khalifa et al. [6] |
|---|---|---|---|---|
| Year/country of publication | 2002, France | 2006, Switzerland | 2010, Netherlands | 2011, France, Belgium |
| Male: female | 3:1 | 0:1 | 3:0 | 0:4 |
| No of cases | 4 | 1 | 3 | 4 |
| Median age in months at diagnosis (range) | 36–168 | 192 | 9, NA: 2 | 24 (6–48) |
| Patient 1: 36 | Patient 1: 60 | |||
| Patient 2: 132 | Patient 2: 1 | |||
| Patient 3: 168 | Patient 3: 3 | |||
| Patient 4: 144 | Patient 4: 1 | |||
| Ethnicity | Moroccan | Swiss | Moroccan | Moroccan |
| Zygosity | All homozygous | Homozygous | Homozygous | All homozygous |
| Variant | exon 1, 2-bp deletion c.200_201delTT | exon 2, 1-bp deletion (c.358delG) | exon 1, 2-bp deletion c.200_201delTT | exon 1, 2-bp deletion, c.200_201delTT |
| Aminoacid change | p. Phe67Ter | p.Val120fs | p. Phe67Ter | p. Phe67Ter |
| Consanguinity | Yes-3, No-1 | No | Yes | Yes |
| Presentation | ||||
| Jaundice | 4/4 | No | 2/3 | 4/4 |
| Pruritus | 1/4 | No | NA | 4/4 |
| Hepatomegaly | 4/4 | Yes | 2/3 | 1/4 |
| Splenomegaly | 3/4 | No | NA | NA |
| Portal hypertension | 3/4 | No | 1/3 | 2/4 |
| Livertransplantation (age) | 1/4, (8 yr) | No | 1/3 | 1/4 (1 yr) |
| Cholangiography; | 3/4 | Not done | 2/3 | Not done |
| - pattern of neonatal sclerosing cholangitis | Yes | No | ||
| - paucity of bile ducts | Yes | |||
| Ichthyosis; diffuse white scales | 4/4 | Yes | 3/3 | 4/4 |
| Hypotrichosis/Alopecia | 4/4 | Yes | 3/3 | 4/4 |
| Oligodontia/Hypodontia | 2/3, 1NA | NA | NA | 1/4 |
| Enamel hypoplasia | 2/3, 1NA | Yes | NA | 1/4 |
| Mental retardation | 1/3, 1NA | No | NA | 0/4 |
| Gall stone | NA | NA | NA | NA |
| Transient neonatal cholestasis | Yes (1/4) | Yes | Yes (1/3) | Yes (3/4) |
| CLD (3/4) | CLD (2/3) | CLD (Patient1/4) | ||
| Liver biopsy | 3/4 | Yes | 2/3 | 2/4 |
| Extensive fibrosis | 3/3 | NA | 1/3 | 1/2 |
| Bile-duct paucity | 1/3 | NA | 2/3 | 0/2 |
| Bile-duct proliferation | 3/3 | NA | 1/3 | 0/2 |
| Acute hepatitis | NA | Yes | No | 0/2 |
| Cirrhosis | 0/4 | No | No | 0/2 |
| Cholestasis | 3/4 | Yes | Yes | 2/4 |
| Laboratory parameters | ||||
| Vacuolated eosinophils | 3/4, 1 NA | No | NA | None |
| Total Bilirubin (mg/dL) | NA | 20.6 | 2/3 elevated | (7.1-9.1) |
| Direct bilirubin (mg/dL) | NA | 2/3 elevated | 2.8-8.3 | |
| ALT elevation | NA | NA | 3/4 | |
| GGT elevation | NA | NA | 1/4 | |
| Follow-up in months median (IQR) | 174 (72–204) | Resolution of NCS (age NA) but ichthyosis persisted | Eldest patient (9 mo) was last seen at 11 yr, with persistent ichthyosis. Younger brother (age NA) had ichthyosis. Patient3: LT (age NA) | 24 (12-48) |
| Persistent cholestasis, n=2, transient cholestasis, n=1 portal hypertension, n=3, LT, n=1 at an age of 6 yr. Post-LT regression of skin lesion and alopecia | Patient 1: Kasai at 6 wk for suspected BA, LT at 1 yr | |||
| Transient NCS, n=2, portal hypertension, n=2, persistent ichthyosis, n=3 (even after LT) |
| Variable | Kirchmeier et al. [7] | Youssefian et al. [8] | Szepetowski et al. [9] | Nagtzaam et al. [10] | Izurieta Pacheco et al. [11] |
|---|---|---|---|---|---|
| Year/country of publication | 2014, Germany | 2017, Iran | 2017, France | 2018, Netherlands | 2020, Spain |
| Male: female | 1:1 | 1:1 | 1:0 | 0:1 | 0:1 |
| No of cases | 2 | 2 | 1 | 1 | 1 |
| Median age in months at diagnosis (range) | Patient 1: 2 | Patient 1: 120 | 24 | 108 | 1 |
| Patient 2: 420 | Patient 2: 18 | ||||
| Ethnicity | Turkish | Kurdish (Iranian) | Moroccan | Turkish | Moroccan |
| Zygosity | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous |
| Variant | c.181C>T | c.578C>A | exon 1, 2-bp deletion, c.200_201delTT | c.181C>T | exon 1, 2-bp deletion, c.200_201delTT |
| Aminoacid change | p.Gln61X | p.Tyr159Ter | p. Phe67Ter | p.Gln61X | p.Phe67Ter |
| Consanguinity | Yes | Yes | Yes | Yes | Yes |
| Presentation | |||||
| Jaundice | 1/2 | 2/2 | Yes | No | Yes |
| Pruritus | 0/2 | 1/2 | Yes | No | No |
| Hepatomegaly | 0/2 | 1/2 | No | No | No |
| Splenomegaly | 0/2 | 1/2 | No | No | No |
| Portal hypertension | 0/2 | 0/2 | No | No | No |
| Livertransplantation (age) | 0/2 | No | No | No | No |
| Cholangiography; | Not done | Not done | MRCP Normal | Not done | Not done |
| - pattern of neonatal sclerosing cholangitis | |||||
| - paucity of bile ducts | |||||
| Ichthyosis; diffuse white scales | 2/2 | 2/2 | Yes | Yes | Yes |
| Hypotrichosis/Alopecia | 2/2 | 2/2 | Yes | Yes | NA |
| Oligodontia/Hypodontia | NA | 1/2 | No | No | NA |
| Enamel hypoplasia | NA | 1/2 | Yes | Yes | NA |
| Mental retardation | NA | 0/2 | No | No | No |
| Gall stone | NA | 2/2 | No | NA | NA |
| Transient neonatal cholestasis | Yes (2/2) | Yes (2/2) | Yes | No | Yes |
| Liver biopsy | Not done | 1/2 | Yes | Not done | Not done |
| Extensive fibrosis | No | No | |||
| Bile duct paucity | No | No | |||
| Bile duct proliferation | No | Yes | |||
| Acute hepatitis | No | No | |||
| Cirrhosis | No | No | |||
| Cholestasis | Yes | Yes | |||
| Laboratory parameters | |||||
| Vacuolated eosinophils | NA | NA | NA | NA | NA |
| Total Bilirubin (mg/dL) | Elevated | Elevated | 5.4 | Normal | 7.1 |
| Direct bilirubin (mg/dL) | Elevated | Elevated | 4.9 | Normal | 5.3 |
| ALT elevation | Elevated | 87-142 | 216 | Normal | 103 |
| GGT elevation | Elevated | Normal | 72 | Normal | 38 |
| Follow-up in months median (IQR) | Patient 1: 17 mo | NA | At 29 mo, pruritus resolved with topical treatment and LFT normalized | NA | Normalization of LFT at 6 mo of age, at last follow-up at 15 mo of age, ichthyosis persisted |
| Transient NCS, n=2, resolved at 3 and 6 mo |
| Variable | Semwal et al. [12] | Alsafri et al. [13] | Demir et al. [14] | Salik et al. [15] | Mohamad J et al. [16] | Bourkas et al. [17] |
|---|---|---|---|---|---|---|
| Year/country of publication | 2022, India | 2020, Paris | 2022, Turkey | 2022, Belgium | 2022, Israel | 2022, Canada |
| Male: female | 1:0 | 0:1 | 1:0 | 0:2 | 0:2 | 0:1 |
| No of cases | 1 | 1 | 1 | 2 | 2 | 1 |
| Median age in months at diagnosis (range) | 6 | 1 | 26 | Patient 1: 1 | Patient 1: 396 | 1 |
| Patient 2: 144 | Patient 2: 624 | |||||
| Ethnicity | Indian | Moroccan | NA | Moroccan | Jewish | Pakistani and Indian |
| Moroccan | ||||||
| Zygosity | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous |
| Variant | chr3: g.190322066G>T | Del exons 2 to 4 | c.89G>A | exon 1, 2-bp deletion, c.200_201delTT | c.242G>A | 16,516 base pair deletion involving exon 1 and the initiation codon of CLDN1 |
| Amino acid change | p.Tyr47Ter | NA | p.Trp30Ter | p.Phe67Ter | p.Arg81His | Premature stop codon |
| Consanguinity | No | Yes | Yes | No | No | No |
| Presentation | ||||||
| Jaundice | Yes | Yes | Yes | 0/2 | 1/2 | Yes |
| Pruritus | Yes | No | Yes | 0/2 | 2/2 | No |
| Hepatomegaly | Yes | Yes | No | 0/2 | 1/2 | No |
| Splenomegaly | Yes | No | No | 0/2 | NA | No |
| Portal hypertension | No | No | No | 0/2 | NA | No |
| Livertransplantation (age) | No | No | No | 0/2 | 1/2 | No |
| Cholangiography; pattern of neonatal sclerosing cholangitis | not done | Not done | Not done | Not done | Not done | Not done |
| Ichthyosis; diffuse white scales | Yes | Yes | Yes | 2/2 | 2/2 | Yes |
| Hypotrichosis/alopecia | Yes | Yes | Yes | 2/2 | 0/2 | Yes |
| Oligodontia/Hypodontia | NA | Dentition not achieved | Yes | 0/2 | 0/2 | Dentition not achieved |
| Enamel hypoplasia | NA | Yes | 1/2 | 0/2 | ||
| Mental retardation | No | No | 2/2 | NA | ||
| Gall stone | NA | No | NA | NA | NA | NA |
| Transient neonatal cholestasis | Yes | NA | Yes | No | No (Patient 2) | Yes |
| CLD (Patient 1) | ||||||
| Liver biopsy | Yes | NA | Yes | Not done | NA | Not done |
| Extensive fibrosis | Yes | No | ||||
| Bile-duct paucity | No | No | ||||
| Bile-duct proliferation | No | Yes | ||||
| Cirrhosis | No | No | ||||
| Laboratory parameters | Patient 2 | |||||
| Vacuolated eosinophils | NA | NA | NA | NA | NA | NA |
| Total Bilirubin (mg/dL) | Elevated | NA | Elevated | Normal, 2/2 | Normal | 7 |
| Direct bilirubin (mg/dL) | Elevated | 1.1 | Elevated | Normal, 2/2 | Normal | 5.6 |
| ALT elevation (IU/L) | Elevated | 130 | Elevated | Normal, 2/2 | Normal | NA |
| GGT elevation (IU/L) | Elevated | Normal | Elevated | Normal, 2/2 | Normal | 62 |
| Follow-up in months median (IQR) | 12, LFT, pruritus resolved but ichthyosis persisted | NA | Bilirubin normalized at 5 mo and transaminases at 3 yr | Patient 1: 24 mo neurodevelopmental delay present | 33 Yr | 7 Mo |
| NCS, diagnosed | Ichthyosis improved, LFT normalized | |||||
| as BA and underwent LT in early childhood |
| Variable | Eskin-Schwartz et al. [18] | Mathew J et al. [19] | Cai L et al. [20] | Danish et al. [21] | Our case |
|---|---|---|---|---|---|
| Year/country of publication | 2023, Israel | 2023, India | 2023, China | 2024,India | 2024, India |
| Male: female | 3:4 | 1:0 | 1:0 | 1:0 | 0:1 |
| No of cases | 7 | 1 | 1 | 1 | 1 |
| Median age in months at diagnosis (range) | 288 (12–636) | 96 | 36 | 48 | 2 |
| Patient 1: 60 | |||||
| Patient 2: 1 | |||||
| Patient 3: 456 | |||||
| Patient 4: 636 | |||||
| Patient 5: 288 | |||||
| Patient 6: 240 | |||||
| Patient 7: 564 | |||||
| Ethnicity | Jewish Moroccan-6 TunisianAlgerian-1 | Indian | Chinese Han | NA | Indian |
| Zygosity | All homozygous | Homozygous | Homozygous | Homozygous | Homozygous |
| Variant | c.242G>A variant (all) | c.141del | c.504_505ins CTGCTGGG | exon 1 variant c.191G>T | c.36dupT |
| Amino acid change | p.Arg81His | p.Tyr47Ter | p.W169Lfs*69 | p.Cys 64Phe | p.Leu13SerfsTer56 |
| Consanguinity | None | No | Yes | Yes | No |
| Presentation | |||||
| Jaundice | 3/7 | No | Yes | Yes | Yes |
| Pruritus | 1/7 | No | No | Yes | Yes |
| Hepatomegaly | NA | No | No | Yes | Yes |
| Splenomegaly | NA | No | No | No | Yes |
| Portal hypertension | 1/7 | No | No | No | No |
| Livertransplantation (age) | 1/7, (8yr) | No | No | Awaiting LT | No |
| Cholangiography; pattern of neonatal sclerosing cholangitis | NA | Not done | Not done | Not done | Not done |
| Ichthyosis; diffuse white scales | 7/7 | Yes | Yes | Yes | Yes |
| Hypotrichosis/alopecia | 3/6, 1NA | Yes | Yes | Yes | Yes |
| Oligodontia/Hypodontia | 5/6, 1NA | No | No | Yes | Dentition not achieved |
| Enamel hypoplasia | 5/6, 1NA | Yes | No | Yes | Dentition not achieved |
| Mental retardation | NA | No | No | No | No |
| Gall stone | 2/7 | No | |||
| Transient neonatal cholestasis | 2/7 (Patient 1, 4) | Yes | Yes | No, CLD | Yes |
| CLD (Patient 3) | |||||
| Liver biopsy | 1/7 | Not done | Not done | Yes | Not done |
| Extensive fibrosis | Yes | No | |||
| Bile duct paucity | No | No | |||
| Bile duct proliferation | No | No | |||
| Cirrhosis | Yes | No | |||
| Laboratory parameters | NA | ||||
| Vacuolated eosinophils | 1 No, 06 NA | No | NA | NA | |
| Total Bilirubin (mg/dL) | NA | NA | 7.1 | 7.5 | |
| Direct bilirubin (mg/dL) | NA | NA | 5.2 | 6.9 | |
| ALT elevation (IU/L) | NA | 64 | 306 | ||
| GGT elevation (IU/L) | NA | 88 | 62.6 | ||
| Follow-up in months median (IQR) | Patient 3: clinically diagnosed as BA, cholecystoporto-hepatic anastomosis done at 2 mo & cholecystojejuno anastomosis at 7 yr), LT at 8 yr | NA | NA | Diagnosed as BA, Hepatoporto-enterostomy done at 1 mo of age, CLD by 4 yr of age | 9 Mo, ichthyosis & pruritus resolved, LFT improving, bilirubin normalized |
Table 2.
Differential diagnoses for patients presenting with cholestasis and ichthyosis
- References
- 1. Feldmeyer L, Huber M, Fellmann F, Beckmann JS, Frenk E, Hohl D. Confirmation of the origin of NISCH syndrome. Hum Mutat 2006;27:408–10.
[Article] [PubMed]2. Baala L, Hadj-Rabia S, Hamel-Teillac D, Hadchouel M, Prost C, Leal SM, et al. Homozygosity mapping of a locus for a novel syndromic ichthyosis to chromosome 3q27-q28. J Invest Dermatol 2002;119:70–6.
[Article] [PubMed] [PMC]3. Hadj-Rabia S, Baala L, Vabres P, Hamel-Teillac D, Jacquemin E, Fabre M, et al. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Gastroenterology 2004;127:1386–90.
[Article] [PubMed]4. Nagtzaam IF, van Geel M, Driessen A, Steijlen PM, van Steensel MA. Bile duct paucity is part of the neonatal ichthyosis-sclerosing cholangitis phenotype. Br J Dermatol 2010;163:205–7.
[Article] [PubMed]5. Paganelli M, Stephenne X, Gilis A, Jacquemin E, Henrion Caude A, Girard M, et al. Neonatal ichthyosis and sclerosing cholangitis syndrome: extremely variable liver disease severity from claudin-1 deficiency. J Pediatr Gastroenterol Nutr 2011;53:350–4.
[Article] [PubMed]6. Khalifa C, Boliaki Botombe G, Stephenne X, Veyckemans F. Anesthetic care of 2 siblings with neonatal ichthyosis and sclerosing cholangitis syndrome: case reports. A A Pract 2018;11:216–8.
[Article] [PubMed]7. Kirchmeier P, Sayar E, Hotz A, Hausser I, Islek A, Yilmaz A, et al. Novel mutation in the CLDN1 gene in a Turkish family with neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome. Br J Dermatol 2014;170:976–8.
[Article] [PubMed]8. Youssefian L, Vahidnezhad H, Saeidian AH, Sotoudeh S, Zeinali S, Uitto J. Gene-targeted next-generation sequencing identifies a novel CLDN1 mutation in a consanguineous family with NISCH syndrome. Am J Gastroenterol 2017;112:396–8.
[Article] [PubMed]9. Szepetowski S, Lacoste C, Mallet S, Roquelaure B, Badens C, Fabre A. Le syndrome NISCH, une cause rare de cholestase néonatale : à propos d’un cas [NISCH syndrome, a rare cause of neonatal cholestasis: a case report]. Arch Pediatr 2017;24:1228. –34. French.
[PubMed]10. Nagtzaam IF, Peeters VP, Vreeburg M, Wagner A, Steijlen PM, van Geel M, et al. Novel CLDN1 mutation in ichthyosis-hypotrichosis-sclerosing cholangitis syndrome without signs of liver disease. Br J Dermatol 2018;178:e202. –3.
[Article] [PubMed]11. Izurieta Pacheco AC, Monfort Carretero L, Prat Torres C, García-Alix Pérez A, Molera Busoms C. NISCH syndrome: an extremely rare cause of neonatal cholestasis. J Hepatol 2020;73:1257–8.
[Article] [PubMed]12. Semwal P, Akhil Raj MS, Bhat NK, Verma PK. NISCH syndrome as a cause of neonatal cholestasis - a case report from India. J Clin Exp Hepatol 2022;12(Supplement 2): S79.
[Article] [PMC]13. Alsafri MS, Charbit-Henrion F, Bourrat E, Steffann J, Hadj-Rabia S. Novel CLDN1 deletion associated with ichthyosis, sclerosing cholangitis and acquired alopecia. Acta Derm Venereol 2020;100:adv00173.
[Article] [PubMed] [PMC]14. Demir E, Tuna Kirsaçlioğlu C, Saltik-Temizel İN, Ürel-Demir G, Karaosmanoğlu B, Taşkiran EZ, et al. Neonatal ichthyosis-sclerosing cholangitis syndrome: report of a novel mutation and a review of the literature. Clin Dysmorphol 2023;32:88–91.
[Article] [PubMed]15. Salik D, Hadj-Rabia S, Hohl D, Vahidnezhad H, Youssefian L, Rakosi A, et al. Evaluation of neurodevelopmental symptoms in 10 cases of neonatal ichthyosis and sclerosing cholangitis syndrome. Pediatr Dermatol 2022;39:590–3.
[Article] [PubMed]16. Mohamad J, Samuelov L, Assaf S, Malki L, Malovitski K, Meijers O, et al. Autosomal recessive congenital ichthyosis caused by a pathogenic missense variant in CLDN1. Am J Med Genet A 2022;188:2879–87.
[Article] [PubMed]17. Bourkas AN, Pope E, Mendoza-Londono R, Kamath BM, Lara-Corrales I. Early diagnosis of ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis syndrome: a case report. Pediatr Dermatol 2023;40:710–2.
[Article] [PubMed]18. Eskin-Schwartz M, Dolgin V, Didkovsky E, Aminov I, Pikovsky A, Hadar N, et al. CLDN1 Arg81His founder variant causes ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome in Moroccan Jews. Clin Genet 2024;105:44–51.
[PubMed]19. Mathews J, Chandrasekaren A. Neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome with a novel Claudin-1 (CLDN1) mutation: a report from India. Indian J Dermatol Venereol Leprol 2025;91:89–91.
[Article] [PubMed]20. Cai L, Lin Z, Wang H. A novel CLDN1 variant identified in a case of ILVASC with sparse curly hair. Clin Exp Dermatol 2023;48:794–5.
[Article] [PubMed]21. Danish M, Choudhary R, Bhari N. Unveiling a novel gene mutation in neonatal ichthyosis-sclerosing cholangitis syndrome with progressive liver disease. Indian J Dermatol Venereol Leprol 2024;Oct 14 1-3. doi: 10.25259/IJDVL_436_2024. [Epub].
[Article]22. João SM, Arana-Chavez VE. Tight junctions in differentiating ameloblasts and odontoblasts differentially express ZO-1, occludin, and claudin-1 in early odontogenesis of rat molars. Anat Rec A Discov Mol Cell Evol Biol 2004;277:338–43.
[PubMed]23. Zorn-Kruppa M, Vidal-Y-Sy S, Houdek P, Wladykowski E, Grzybowski S, Gruber R, et al. Tight Junction barriers in human hair follicles - role of claudin-1. Sci Rep 2018;8:12800.
[Article] [PubMed] [PMC]24. Sakisaka S, Kawaguchi T, Taniguchi E, Hanada S, Sasatomi K, Koga H, et al. Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2001;33:1460–8.
[Article] [PubMed]25. Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol 1989;13 Suppl 1:43–9.
[PubMed]