Distal Arthrogryposis: A Clue to the Etiology of Neonatal Cholestasis
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SCIENTIFIC LETTER
Distal Arthrogryposis: A Clue to the Etiology of Neonatal Cholestasis Archana Rai 1 & Kausik Mandal 1 & Deepti Saxena 1 & Meenakshi Lallar 1 & Shubha R Phadke 1 Received: 19 September 2019 / Accepted: 12 February 2020 # Dr. K C Chaudhuri Foundation 2020
To the Editor: Neonatal cholestasis is a diagnostic challenge as it is a presentation of various disorders, mostly genetic in origin, and clinical clues to etiology are usually missing. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive rare multisystem disorder with cholestasis as a prominent feature. Here, we report two cases with ARC syndrome. Case1 was a 3-mo-old female with 2.15 kg weight (Z score -7.77), 49 cm length (Z score -4.73) and 32 cm head circumference (Z score -6.26). She was the first child of third degree consanguineous parents. She was presented with jaundice and pale stools. She had severe growth retardation, loose, dry and scaly skin. Microcephaly and developmental delay was present. She was presented with distended abdomen, upslanting eyes, clinodactyly, contractures of interphalangeal joints and fixed dorsiflexion at both ankle joints. Total serum bilirubin level was 9.4 mg/dl with mainly conjugated hyperbilirubinemia of 6.9 mg/dl. Total cholesterol and triglyceride level were 120 mg/dl and 265 mg/dl respectively. Serum glutamic pyruvic transaminase was 191 u/L and serum glutamic oxaloacetic transaminase was 130 u/L. Gamma-glutamyl transferase value was 31 u/L. Case 2 was a 27-d-old male child with 3 kg weight (Z score of -2.36), 48 cm length (Z score of -3.45) and 34 cm head circumference (SD -2). He was the third child of consanguineous parents. He had yellowish skin discoloration, dark yellow urine, acholic stools and failure to
* Shubha R Phadke [email protected] 1
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
thrive, renal tubular acidosis, micrognathia and arthrogryposis. Serum bilirubin and conjugated serum bilirubin level were 20.4 mg/dl and 15.2 mg/dl respectively. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase and alkaline phosphatase were 29 u/L, 42 u/L and 952 u/L respectively. Both these patients presenting with neonatal cholestasis had additional finding of joint contractures, suggesting diagnosis of Arthrogryposis-renal dysfunction-cholestasis syndrome. Next generation sequencing revealed previously reported [1] homozygous variant LRG_884: c.558_559delCT in VPS33B gene (ClinVar accession SCV000902241) in case 1 and novel homozygous variant NM_001193314.1; c.618_626dup in VIPAR gene (ClinVar accession SCV000902240) in case 2. Both variants were classified as likely pathogenic variants according to ACMG guidelines [2]. Both sets of parents were found to be heterozygous for the respective variants. Presence of arthrogryposis is a clinical clue to the diagnosis which is helpful even in next generation sequencing (NGS) era. Identification of pathogenic sequence var
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