Discussion:
CNS is a rare hereditary disorder characterized by an inborn metabolic defect 3. There are two types of Crigler Najjar Syndrome (CNS): type I and type II. The underlying problem in both forms is the absence or significantly reduced quantity of the enzyme UDP-glucuronosyltransferase due to mutations in the UGT1A1 gene4 . Type I CNS, the most dangerous kind, is characterized by a total deficiency of the enzyme UGT1A1 and affects infants from birth, with only a small percentage of children living through infancy before dying to bilirubin encephalopathy. Type II CNS, also known as Arias syndrome, is a less severe form of CNS resulting from a partial lack of the enzyme, with affected people having a much longer life expectancy 5 . Individuals with CN type II have serum bilirubin levels of 10 to 20 mg/dL (175 to 350 mol/l) and rarely acquire kernicterus. However, neurological impairment can develop if hyperbilirubinemia is aggravated by fasting, medications, or viral illnesses [6] . Although there are reported differences in the inheritance pattern of type II CNS, Crigler Najjar syndrome is mostly autosomal recessive 4 . It’s critical to distinguish between Crigler-Najjar syndrome types I and II. The use of phenobarbital, a barbiturate that lowers blood bilirubin levels, is indicated for Crigler Najjar syndrome type II. For patients with syndrome type I, however, this medication is ineffective. As a result, failure to react to this medicine is a crucial indicator for accurate diagnosis 7 . Studies worldwide suggest an estimated prevalence of 1 per million live births for both forms of CNS and are believed to impact people of all races and genders similarly8.
Furthermore, we conducted a thorough review and collated all CN types I and II cases, considering their age, gender, disease onset, type of CN syndrome, clinical features, laboratory findings, associated diseases, and treatment/outcomes. In addition, we conducted a thorough literature search on Pubmed using the terms ’Crigler Najjar syndrome, ‘phenobarbital,’ ‘outcomes.’ The study included all case reports and case series of age limits (from birth to 18 years of age) from the past decade (2010 to 2022). Articles that lacked extractable clinical data and a description of individual data were eliminated. The titles and abstracts of the retrieved publications were used to determine their eligibility. The eligibility criteria were met by 12 papers involving 14 patients (Table 3) .
In our case, a 14-year-old boy demonstrated features consistent with unconjugated hyperbilirubinemia. Later, on adding phenobarbital therapy, a drastic fall in the bilirubin levels was noted, and he was diagnosed with Crigler-Najjar syndrome type II (CNS II). Along with CNS II, he had celiac disease. This rare co-existing condition was associated with a significant decrease in his Hemoglobin levels, hematocrit, MCV, and MCHC. In addition, the presence of tear-drop (dacrocytes) cells in his peripheral smear indicated Severe Iron deficiency.
Unfortunately, due to fewer limitations in Pakistan, the diagnosis was made by unconjugated hyperbilirubinemia and family history. Clinically suspected cases of CNS should undergo serum unconjugated bilirubin level testing. Levels of unconjugated bilirubin vary in both CNS I and II. Higher levels between 20 to 25 mg/dL were noted in type I, whereas in CNS type II, bilirubin is usually less than 20 mg/dL4. Diagnosis can be made, using bile analysis technique revealing no detectable bilirubin glucuronides or urine analysis may demonstrate a lack of bilirubin. CNS I and II can be differentiated by bile pigment analysis and by discerning the response of serum bilirubin levels to phenobarbital therapy9 .
In patients with CNS type II, treatments include phenobarbital therapy, light therapy, plasmapheresis, enzyme, and liver transplantation. Light therapy, also known as phototherapy, effectively decreases unconjugated bilirubin by causing its excretion in bile and converting it to a water-soluble photo isomer 10 . Patients seldom require exchange transfusions or long-term phototherapy11 . In our case, the addition of phenobarbital resulted in a marked improvement of icterus. Furthermore, a slight decline in his liver enzyme GGT and ALP was noted.
The gene encoding for bilirubin UDP-glucuronosyltransferase in conditions like Crigler-Najjar syndromes I and II and Gilbert’s syndrome are affected. The usual investigative measures for these cases include molecular genetic testing, which reveals the genetic mutation in patients with these conditions. A better understanding of genetics-based on molecular diagnosis will improve the diagnostic efficiency and gain informed genetic counseling for any acquired disorder characterized by unconjugated hyperbilirubinemia. 12 .