A male neonate was born small for gestational age with a birthweight of 2.36 kg to a 32-year-old gravida 2 woman in a third-degree consanguineous marriage. The mother’s history included a spontaneous abortion at 10 weeks of gestation in the previous pregnancy. The current pregnancy was a product of spontaneous conception. The antenatal period in this pregnancy was uneventful, with regular follow-ups. The mother also took iron and folic acid supplementation along with tetanus toxoid immunization. She has no history of fever, rash, or any teratogenic exposure during pregnancy. Screening for gestational diabetes, hypertension, and thyroid disorders in this pregnancy found no abnormalities. Targeted imaging for fetal anomalies at 20 weeks of gestation had normal findings. Subsequent growth scans showed polyhydramnios but the growth pattern was appropriate for gestational age. The neonate was delivered at 37 weeks and 6 days of pregnancy via emergency caesarean section in view of decreased fetal movements. The amniotic fluid was clear at the time of birth. The neonate did not cry immediately after birth and required positive pressure ventilation for 30 seconds. His Apgar scores were 7, 8, and 8 at 1, 5, and 10 minutes, respectively. Cord arterial blood gas analysis revealed a pH of 7.23, base excess −5.6 mmol/L, Pco2 46 mm Hg (6.12 kPa), Po2 24 mm Hg (3.19 kPa), and lactate 1.8 mmol/L (0.2 mmol/L). There is no significant history suggestive of unexplained death or any genetic disease in other family members.In view of the respiratory distress, the neonate was transferred to the NICU. Oxygen support was started in the form of nasal prongs. Vital signs on examination were as follows: heart rate 128 beats/min, respiratory rate 62 breaths/min, temperature 97.7°F (36.5°C), oxygen saturation 98% via nasal prongs, and blood pressure 66/50 mm Hg (mean 42 mm Hg). On examination, the neonate’s weight, length, and head circumference were 2,360 g (5th percentile), 48 cm (30th percentile), and 32.5 cm (20th percentile), respectively. On general examination, facial dysmorphism was noted in the form of large fontanels with wide sutures, low-set ears, hypertelorism, periorbital puffiness with hazy cornea, depressed nasal bridge with broad nose, and high arched palate (Fig 1A). There was a redundant skinfold over the nape of the neck. Simian crease and bilateral clubfoot were also noted (Fig 1B). The testes were undescended. Detailed neurologic examination revealed a lethargic neonate with diminished arousal response and markedly diminished motor responses. Deep tendon reflexes were also difficult to elicit, with weak cry and poor sucking and swallowing reflex. The neonate was grossly hypotonic with significant head lag and shoulder hypotonia (Fig 1C). Pooling of secretions was also noted, with minimal response to light and sound. Abdominal examination revealed a firm liver that was palpable 2 cm below the right subcostal margin with a smooth surface and no splenomegaly.As breathing became shallow and respiratory distress increased, with oxygen saturation falling below 90%, the neonate was moved to oxygen via high-flow nasal cannula with a flow of 6 L/min. The breathing pattern improved later and respiratory supports were weaned off. The neonate was moved on free flow oxygen intake to the mother’s side in a postnatal room. Supportive therapies were started in the form of oromotor stimulation, physiotherapy, and non-nutritive sucking. Gradually, he started to feed through a cuplike utensil with a narrow tip used for feeding in India (“paladai”) from day 3. Minimal improvement was seen in tone and level of consciousness by day 7. He was discharged on day 15 after birth after the mother learned how to care for him. He developed seizures at 1 month of age, which required readmission, and he was started on antiseizure medication. He did not attain any milestones on follow-up and died at 5.5 months of age due to respiratory illness.The neonate was initially evaluated with arterial blood gas analysis, sepsis screening, measurement of serum glucose, calcium, and electrolytes, and expanded newborn screening for neonatal sepsis and metabolic derangements. Laboratory investigation revealed normal arterial blood gas analysis, sepsis screening (total white blood cell count 4,000/μL [4 × 109/L], C-reactive protein 0.04 mg/dL [0.4 mg/L]), and basic metabolic panel (serum glucose 65 mg/dL [3.6 mmol/L], total serum calcium 9.7 mg/dL [2.4 mmol/L], serum sodium 141 mEq/L [141 mmol/L], and serum potassium 4.2 mEq/L [4.2 mmol/L]). Liver function parameters revealed a total bilirubin of 7.8 mg/dL (133.4 μmol/L], aspartate aminotransferase 24 U/L (0.4 μkat/L), and alanine aminotransferase 34 U/L (0.6 μkat/L). Thyroid-stimulating hormone was 1.45 µIU/mL on day 3. Titers for toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex (TORCH) syndrome were also within normal limits. Findings of expanded newborn screening and tandem mass spectrometry were normal, with no metabolic derangements. Total creatine phosphokinase level was 158 U/L (2.6 μkat/L; reference value <652 U/L [10.9 μkat/L]). Neurosonography revealed bilateral pseudocysts of germinal matrix with mild ventriculomegaly. Ophthalmologic evaluation revealed hypopigmented iris and fundus with hazy cornea. Two-dimensional echocardiography indicated a 1-mm closing patent ductus arteriosus on day 2. Abdominal ultrasonography revealed mild hepatomegaly with bilateral mild pelviectasis in the kidneys without any cystic changes. Skeletal survey showed a narrow chest (Fig 2A) with punctuate calcifications at the knee joint (Fig 2B). Magnetic resonance imaging (MRI) and genetic testing confirmed the diagnosis.Brain MRI showed cysts in the caudothalamic groove bilaterally, abnormal sulcation in the frontal and parietal lobes with extensive polymicrogyria of both, and sylvian fissure with no evidence of hypoxic injury (Fig 3A and 3B). Based on all these findings, a presumptive diagnosis of peroxisomal disorder was made.Clinical exome sequencing showed a pathogenic homozygous variant, c.589C>T (p.Gly197Ter) (NM_001199319), in exon 4 of the PEX26 gene known to cause Zellweger syndrome. This variant was absent from population databases with low minor allele frequency in the in-house database. In-silico predictions reported it to be damaging, with a combined annotation-dependent depletion score of 36.0, and a codon that was conserved across mammalian species. This variant was consistent with the presumptive diagnosis of the child. Both parents are heterozygous carriers for the same variant identified in the child.Peroxisomal disorders comprise a wide spectrum of clinically and genetically heterogenous disorders. They are classified into 2 subgroups: peroxisome biogenesis disorders and single peroxisomal enzyme deficiency. The prototype of peroxisomal biogenesis disorders is classic Zellweger syndrome. Zellweger syndrome, also known as cerebrohepatorenal syndrome, is a rare genetic disorder which comes under the group of peroxisomal biogenesis disorder.It is an autosomal recessive disorder characterized by a defect in peroxisome biogenesis caused by a mutation in one of the PEX genes (1). PEX genes encode proteins called peroxins and are involved in either peroxisome formation or peroxisomal protein import or both (2). These mutations in PEX genes result in deficiency of functional peroxisomes. These gene defects were earlier named to the spectrum of disorders known as Zellweger syndrome, neonatal adrenoleukodystrophy (ALD), infantile Refsum disease, and rhizomelic chondrodysplasia punctata. (3) Among the first 3 disorders, Zellweger syndrome is the most severe, infantile Refsum the least severe, and neonatal ALD is of intermediate severity. Defective peroxisomal function can lead to impaired fatty acid metabolism, leading to the accumulation of very long chain fatty acids, phytanic and pristanic acids, C27-bile acid intermediates, and pipecolic acid in plasma, and can have deficiency of plasmalogens in erythrocytes. (4) Accumulation of all these metabolites leads to multiorgan dysfunction including neurodevelopmental delay, liver dysfunction, developmental delay, adrenocortical dysfunction, and hearing and vision impairment.Facial profile is also characteristic in the early phase of infancy. (5) In our case, the neonate’s facial profile was not similar to that seen with Zellweger syndrome, but he had central hypotonia and characteristic MRI brain findings. (6) Increased levels of very long chain fatty acid and phytanic acid and urinary metabolites like pipecolic acid were not detected in our case. Patients with mild Zellweger syndrome disorders may have near-normal biochemical findings in plasma and urine. (7)(8) Among the differential disorders to consider, single peroxisomal enzyme deficiencies especially Acyl-CoA oxidase type 1 deficiency and D-bifunctional protein deficiency show several overlapping clinical features. (9)(10)At present, there is no curative treatment for Zellweger syndrome. Treatment is mainly supportive like ensuring proper calorie intake by means of a proper feeding protocol, physiotherapy, and early stimulation and interventions for sensory and motor system and intake of fat-soluble vitamins with phytanic acid–restricted diet. Holistic care requires involvement of a multidisciplinary team including pediatricians, neurologists, audiologists, ophthalmologists, and orthopedists. Preventive measures should be taken against acquiring respiratory tract infections. The cause of death usually is gastrointestinal bleeding and liver failure.Zellweger syndrome should be considered in the differential diagnosis of a neonate with central hypotonia with dysmorphism. Confirmation of the diagnosis requires good clinical expertise with adequate collaborative efforts of the neonatologist, geneticist, pediatric neurologist, and radiologist.