A full-term (40 1/7 weeks) male infant with a birthweight of 3.630 kg is delivered via lower-segment cesarean section by a 31-year-old primigravida woman. Prenatal screening was unremarkable and showed her to be VDRL nonreactive, HBsAg negative, rubella immune, and human immunodeficiency virus nonreactive. The pregnancy is complicated by increased nuchal translucency at 13 weeks which is followed by amniocentesis revealing normal karyotype and polyhydramnios by 32 weeks. The infant cries immediately after birth with normal Apgar scores noted upon birth. Physical examination shows generalized floppiness (Fig 1) with multiple facial dysmorphisms, ie, high forehead, depressed nasal bridge, hypertelorism, bilateral dysplastic ears, high-arched palate, and micrognathia (Fig 2). In addition, a plethora of abnormal physical findings are noted, including wide open anterior fontanelle, large posterior fontanelle with separated sutures, bilateral corneal edema/cloudiness, redundant fold of skin over neck, widely spaced nipples, bilateral undescended testis, and bilateral congenital talipes equinovarus. Over the first several postnatal days, he requires noninvasive respiratory support with intermittent mechanical ventilation initially for retained lung fluids, and later, for inability to maintain airway and generalized hypotonia. Chest radiography performed for respiratory distress is marked by epiphyseal stippling at the hip joint (head of femur) bilaterally (Fig 3).Ultrasonography reveals no structural anomaly of the skull, but in the abdomen and kidney, ureter, and bladder region, bilateral echogenic kidneys are noted, suggesting cortical cysts with normal corticomedullary differentiation.In view of normal karyotype found via amniocentesis, generalized hypotonia, and epiphyseal stippling on radiography, a range of tests is requested. Plasma very long chain and branched chain fatty acids reveal elevated C26:0- 0.92 (0.23+/−0.09 microg/ml) and C26/C22: 0.05 (0.01±0.004), whereas serum phytanic acid, pristanic acid, C22 0, and C24 0 are within normal limits. Further, serum pipecolic acid level is 376.65 μmol/L (range, 0.7–2.5 μmol/L) and plasmalogen-to-fatty acid ratio indicates normal C16:0 DMA/C16:0 fatty acid 0.054 (0.021–0.070) and low C18:0 DMA/C18:0 fatty acid ratios 0.022 (0.027– 0.120).Molecular genetic testing study reveals a novel mutation of PEX6 gene. A homozygous 2–base pair deletion in exon 13 of the PEX6 gene (chr6:42933525_42933526delAC; Depth: 117x) resulting in a frameshift and premature truncation of the protein 14 amino acids downstream to codon 789 (p.Phe789CysfsTer14; ENST00000304611) is detected. Sequencing analysis of the parents shows heterozygous state for this novel mutation of c.42933525_42933526delACof PEX6.Increased nuchal translucency is considered to be a marker of chromosomal anomalies. But the same without aneuploidy is not completely innocuous. These cases may present with fetal akinesia, intrathoracic and extrathoracic compressive syndromes (ie, if there is abnormally narrow thoracic cage or an intrathoracic lesion such as a diaphragmatic hernia), orofacial cleft defects, body stalk anomalies, and structural anomalies, including cardiac defects. (1)(2)However, a substantial number of such fetuses have no anomalies and good neonatal outcome. Vieira et al (3) found normal karyotype in 54.4% of 116 cases of nuchal translucency above the 95th percentile (only 68% had conventional karyotype available). Normal births and immediate postnatal development were observed in 93% of these fetuses. Socolov et al (4) reported that of 58 euploid cases, 40 (69%) had normal outcome and 18 (31%) had adverse outcomes (miscarriages, cardiac abnormalities, or complications due to prematurity).Generally, syndromes that result in profound neonatal hypotonia, (ie, Down syndrome, Prader Willi syndrome, Lowe syndrome) do not cause epiphyseal stippling. Stippled epiphysis is seen in rhizomelic chondrodysplasia punctata (RCDP), Zellweger syndrome, Conradi-Hünermann syndrome, warfarin embryopathy, alcohol-related embryopathy, maternal mixed connective tissue disorder, and maternal systemic lupus erythematosus (SLE). (5) Cases are described in which mothers with high-titer antiribonucleoprotein antibodies and maternal SLE have fetuses with chondrodysplasia punctata and no identifiable genetic disorder, biochemical deviation, or history of teratogen exposure. (5)With normal karyotype in amniocentesis, neonatal hypotonia, characteristic facial features, and epiphyseal stippling on radiography, peroxisomal disorders are considered. The diagnosis in the current case was established based on suggestive clinical and biochemical features and identification of a novel mutation of the PEX6 gene. Biallelic pathogenic variants in 1 of 13 known PEX genes are responsible for peroxisomal disorders, of which PEX1, PEX6, and PEX12 account for the majority, whereas PEX11B is least frequent. (6) Peroxisome biogenesis disorder 4A, also known as Zellweger syndrome (OMIM#614862) and peroxisome biogenesis disorder 4B (OMIM#614863) are caused by homozygous or compound heterozygous mutations in the PEX6 gene (OMIM*601498). The in-silico prediction of the variant is damaging by MutationTaster2.This novel mutation of chr6:42933525_42933526delAC is analyzed as the likely cause of the clinical and biochemical features with in silico analysis. This PEX6 variation has not been reported in the 1,000 Genomes database and has a minor allele frequency of 0.002% in the ExAC database.Peroxisomal biogenesis disorder is divided into 2 subtypes: 1) Zellweger spectrum disorder (ZSD), and 2) RCDP spectrum. ZSD includes Zellweger syndrome, which is the most severe; neonatal adrenoleukodystrophy (ALD), of intermediate severity; and infantile Refsum disease, the least severe. Both ALD and infantile Refsum disease have no renal cortical cysts and chondrodysplasia punctata. As a group, ZSD shows elevated plasma concentrations of C26:0 and C26:1; elevated ratios of C24/C22 and C26/C22; elevated phytanic acid and/or pristanic acid; raised pipecolic acid in both plasma and urine; and reduced C16 and C18 plasmalogens. However, in RCDP, levels of plasma very-long-chain fatty acids are normal, but plasma phytanic acid levels are increased and erythrocyte plasmalogen levels are decreased. (6)(7) Two major exceptions in neonatal presentation of ZSDs are normal serum phytanic and pristanic acid levels (minimal dietary intake of phytanic acid in formula and breast-fed infants) and high urinary excretion of pipecolic acid in the neonatal period, leading to the suggestion of urine testing of neonates and plasma testing in older children. (6)On day 19 after birth, following some improvement in tone, the infant was weaned off respiratory support, but he remained dependent on tube feeds and was discharged on day 26 with feeding tube in situ.At 2 months, the infant was admitted again for an episode of fever with urinary tract infection (Klebsiella pneumonia). Later he succumbed to an episode of severe pneumonia at 5 months of age.Fetuses with increased nuchal translucency without aneuploidy, may have fetal akinesia, cardiac defects, intrathoracic and extrathoracic compression and body stalk anomaly.Sometimes initial radiographs obtained for clinical management reveal the diagnosis in floppy neonates.In neonatal presentation of ZSDs, serum phytanic and pristanic acid levels remain normal because of minimal dietary intake of phytanic acid in formula and breast-fed infants.The authors thank Dr S. Chatterji, CEO, Dr LH Hirandani Hospital, Powai, Mumbai, Maharashtra, India, for approving publication of this article.