Prenatal and postnatal diagnosis of congenital ichthyosis: Three Asian-Indian cases

INTRODUCTION

Congenital ichthyosis (CI) belongs to a group of inherited disorders characterized by abnormal skin scaling, which typically presents at or shortly after birth. The severity of CI can vary widely, with manifestations ranging from mild, localized scaling to severe, widespread involvement that significantly affects quality of life. The condition is caused by mutations in genes encoding proteins involved in the formation, function, and turnover of the skin’s epidermal barrier. This leads to impaired skin barrier function, which causes the characteristic scaling, dryness, and thickening of the skin. CI is classified into several subtypes on the basis of inheritance patterns (autosomal recessive, autosomal dominant, or X-linked) and the underlying genetic mutations. Some of the most common forms of CI include lamellar ichthyosis, harlequin ichthyosis, epidermolytic ichthyosis, and steroid sulfatase deficiency. These forms differ in their clinical presentations, ranging from generalized thick, adherent scaling to more localized, less severe forms of scaling. The diagnosis is primarily clinical, but genetic testing and molecular analysis are essential for confirming the specific subtype and for providing genetic counseling.^[1] In addition to skin involvement, CI can be associated with a variety of systemic manifestations, including ocular abnormalities (such as corneal opacities or ectropion), neurological issues, musculoskeletal abnormalities (including skeletal malformations), and hepatic dysfunction (e.g., hepatomegaly, fatty liver, and elevated liver enzymes). Such multisystem involvement is particularly prominent in syndromic forms of CI, such as Chanarin-Dorfman syndrome (CDS), Netherton syndrome (NS), Refsum syndrome, and Chediak–Higashi syndrome. These disorders highlight the importance of a comprehensive approach to diagnosis, as they can present with a combination of cutaneous and systemic features that require multidisciplinary management.^[2] Advances in whole-exome sequencing and other genomic technologies have improved the ability to identify causative mutations, furthering our understanding of the underlying mechanisms of CI. Management of CI is largely supportive and focuses on improving skin hydration, preventing infections, and addressing systemic complications. Topical treatments such as keratolytics, urea-based creams, and emollients are commonly used to manage the skin scaling, while oral retinoids may be indicated in more severe cases. Regular follow-up with dermatology, ophthalmology, and genetics is often necessary to monitor for potential complications and ensure optimal care.^[3] We hereby describe three cases of CI syndrome presenting in early childhood.

CASE REPORT

Case 1

A 19-month-old female, the firstborn of a third-degree consanguineous marriage, presented with xerotic and scaly skin since birth, along with progressive abdominal distension over the past 4 months. The child’s developmental milestones were age-appropriate. On examination, the weight was 8.6 kg (corresponding to −1.6 Z-score), height was 70 cm (−3.9 Z-score), and head circumference was 44 cm (−1.7 Z-score) (according to the WHO growth charts). Cutaneous examination revealed extensive, large, adherent, lamellar scales on the extremities [Figure 1] and finer, grayish, semi-adherent scales on the trunk. The skin appeared taut, xerotic, and was associated with sparse hair and hypohidrosis. Additional dysmorphic features included bilateral ectropion, strabismus [Figure 2], and dysplastic auricles with fusion of the helix and antihelix [Figure 3]. Systemic examination was largely unremarkable except for hepatosplenomegaly. Laboratory investigations revealed elevated transaminases, with aspartate aminotransferase (AST) at 126 U/L and alanine aminotransferase (ALT) at 90 U/L, as well as hypertriglyceridemia (160 mg/dL). Peripheral blood smear analysis showed cytoplasmic vacuolation of neutrophils and eosinophils [Figure 4]. Abdominal ultrasonography confirmed hepatomegaly (13.8 cm), splenomegaly (8.3 cm), and grade 3 hepatic steatosis. Given the combination of ichthyosis, multisystem involvement, and the presence of lipid vacuoles in neutrophils, a diagnosis of CDS was strongly considered. Genetic testing through whole-exome sequencing confirmed the diagnosis, revealing a homozygous pathogenic variant in exon 6 of the ABHD5 gene [c.810T>A: p.(Tyr270*)]. A multidisciplinary approach for management was followed for this case. Skin care with topical retinoids and keratolytic was planned, bilateral inferior oblique muscle weakening was planned for esotropia, and hearing rehabilitation was done. Dietary management plays a crucial role in such cases; hence, medium-chain triglyceride supplementation and fat restriction, along with supplementation with ursodeoxycholic acid (20 mg/kg/day) and Vitamin E (10 mg/kg/day), were started. Genetic counseling explaining the 25% risk of recurrence was done, and the couple was willing to undergo prenatal testing in the next pregnancy.

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Figure 1:

Large, adherent, lamellar scales over the extremities.

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Figure 2:

Bilateral ectropion and strabismus.

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Figure 3:

Dysplastic ears with fusion of helix and antihelix.

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Figure 4:

Peripheral blood smear showing cytoplasmic lipid containing vacuolation in neutrophils suggestive of Jordan anomaly (black arrow).

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Case 3

This baby was antenatally detected in the second trimester of pregnancy on level II ultrasonography to have growth retardation, ambiguous genitalia, club feet, and microcephaly. The parents opted for the termination of the pregnancy. The fetus had an open mouth, thick skin, excoriation over the neck, and swelling over the hands and feet [Figure 5]. X-ray fetogram revealed kyphoscoliosis, abnormal shape of head, and a unilateral short forearm [Figure 6]. A NGS-Whole Exome Sequencing was performed, which revealed a PSAT1 pathogenic variant in exon 6 in a homozygous state c.664 C>T: (p.Arg222Ter), confirming a diagnosis of Neu–Laxova syndrome (NLS).

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Figure 5:

Fetal autopsy showing thick skin, excoriation over the neck, and swelling over the hands and feet.

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Figure 6:

(a) Fetogram AP showing abnormal shape of head, kyphoscoliosis and left side short forearm (blue arrow), (b) Fetogram lateral view showing abnormal shape of head and kyphoscoliosis (blue arrow).

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DISCUSSION

CI refers to a genetically heterogeneous group of inherited keratinization disorders characterized by generalized scaling of the skin, often manifesting at or shortly after birth. While some forms are isolated to the skin, syndromic ichthyosis involves additional systemic features, reflecting underlying genetic abnormalities that affect multiple organ systems.^[5] CI is caused by pathogenic variants in genes that regulate epidermal barrier formation, lipid transport, or keratinocyte differentiation.^[1] Based on inheritance patterns and causative mutations, CI is classified into several subtypes, including lamellar ichthyosis, harlequin ichthyosis, epidermolytic ichthyosis, and steroid sulfatase deficiency. Diagnosis is primarily clinical but requires genetic testing for precise subtype confirmation, prognostication, and counseling.^[6] The first Ichthyosis Consensus Conference categorized ichthyosis into two primary types: Syndromic and non-syndromic. Syndromic ichthyoses may be associated with ocular, neurological, musculoskeletal, and hepatic manifestations. They can be inherited in X-linked, autosomal recessive, or autosomal dominant patterns and are further classified based on predominant associated features such as hair anomalies (e.g., NS), neurological involvement (e.g., Sjögren–Larsson syndrome [SLS]), hearing loss (e.g., Keratitis-Ichthyosis-Deafness syndrome), metabolic defects (e.g., congenital disorders of glycosylation), or multi-organ involvement with severe outcomes (e.g., Arthrogryposis, renal dysfunction, and cholestasis syndrome). Over 30 causative genes have been identified, and early recognition is crucial because some forms allow targeted interventions – such as metabolic correction or cardiac monitoring – that can be life-saving.^[7] In a study done in the Dermatology Department of the Postgraduate Institute, Chandigarh, on congenital syndromic ichthyosis, out of 86 patients with CI, six had a syndromic form (8.1%). These included three patients with Larson syndrome (SLS), two with Netherton syndrome (NS), and one with Chanarin-Dorfman disease.^[8]

CDS is a rare autosomal recessive neutral lipid storage disorder caused by mutations in the ABHD5 (CGI-58) gene on chromosome 3p21. The encoded protein functions as a co-activator of adipose triglyceride lipase, essential for triglyceride hydrolysis. Deficiency results in intracellular triacylglycerol accumulation in multiple organs. Clinically, CDS presents as non-bullous congenital ichthyosiform erythroderma with systemic features such as hepatomegaly, hepatic steatosis, progressive liver dysfunction, myopathy, sensorineural hearing loss, and occasionally cataracts. The condition was first identified by Jordan in 1953 when lipid vacuoles were noted in the leukocytes of two brothers with progressive muscular dystrophy.^[9] Later, Dorfman and Chanarin described a systemic lipid storage disorder in 1975.^[10] Extra-cutaneous involvement is common and includes hepatomegaly, hepatic steatosis, progressive liver dysfunction, myopathy, sensorineural hearing loss, and, occasionally, cataracts.^[2] Our patient had hepatic steatosis, bilateral hearing loss, and squint. Multidisciplinary management, including skin-directed therapy and dietary lipid restriction, resulted in improvement in biochemical and imaging parameters: AST 87 U/L, ALT 65 U/L, triglycerides 132 mg/dL, and a reduction in liver size to 10.8 cm. The diagnosis should be differentiated from other conditions associated with ichthyosis, including NS, SLS, Refsum disease, and Gaucher disease type 2. The severity and outcome of CDS depend on the degree of muscle and liver involvement, with cirrhosis being a potentially life-threatening complication.

Our second case represents non-syndromic ichthyosis with a variation in the NIPAL4 gene. Clinically, it often presents at birth with a collodion membrane or congenital ichthyosiform erythroderma, later evolving into fine to large brown scales, typically sparing skin folds. Palmoplantar keratoderma may also occur. The condition results from defects in epidermal lipid processing, disrupting skin barrier function. Diagnosis is confirmed by genetic testing, and treatment remains symptomatic with emollients, keratolytics, and, in some cases, systemic retinoids. In contrast, NLS represents one of the most severe syndromic ichthyoses, typically lethal in the perinatal period. It is also inherited in an autosomal recessive manner and is primarily associated with mutations in genes PHGDH, PSAT1, and PSPH, which are involved in the L-serine biosynthesis pathway.^[11] L-serine is essential for epidermal renewal, lipid production, and central nervous system development. Deficiency leads to profound cutaneous and neurological abnormalities, including severe ichthyosis, microcephaly, lissencephaly, hydrops, facial dysmorphism, and joint contractures.^[12] In our case, the fetus exhibited growth restriction, ambiguous genitalia, club feet, and microcephaly. Medical termination of pregnancy was undertaken following prenatal diagnosis. With no definitive therapy available, the lethality of the condition management of NLS is limited to supportive or palliative care in live births, highlighting the importance of early antenatal detection and genetic confirmation for counseling.

CONCLUSION

Congenital ichthyosis encompasses a genetically heterogeneous spectrum of disorders, ranging from isolated cutaneous involvement to severe multisystem syndromes. Our cases highlight the diagnostic value of next-generation sequencing in identifying dual or rare genetic defects and refining genotype–phenotype correlations. Syndromic forms such as Chanarin-Dorfman and Neu-Laxova syndromes illustrate the systemic burden of CI, underscoring the importance of molecular confirmation, multidisciplinary care, and genetic counseling in advancing patient management and research.