A337 KABUKI SYNDROME: A NEW ADDITION TO THE DIFFERENTIAL DIAGNOSIS OF LOW-GGT NEONATAL CHOLESTASIS

Neonatal low-GGT cholestasis has a unique differential diagnosis centered on congenital disorders of bile acid transport or synthesis. Kabuki syndrome is a genetic condition with distinctive facies, developmental delay, and skeletal, renal and cardiac defects. While Kabuki has been associated with high-GGT cholestatic conditions including biliary atresia, patients with low-GGT cholestasis have not previously been described. To describe 2 patients with Kabuki syndrome and low-GGT neonatal cholestasis Chart review. Case 1: A female infant of non-consanguinous South Asian parents was born at 35 6/7 weeks. Antenatal US was normal. Facial dysmorphisms and hypotonia were noted at birth. Whole exome sequencing analysis confirmed Kabuki syndrome with de novo deletion in the KMT2D gene. Ventilation was needed from birth, with right-sided heart failure from pulmonary hypertension. She required TPN. Cholestasis was identified at 6 weeks: conjugated bilirubin 175umol/L, AST 404U/L, ALT 121U/L, ALP 289U/L, GGT 64U/L (70–130). Abdominal US: hepatosplenomegaly and ascites without biliary abnormalities. CMV infection occurred at 12 weeks. Liver biochemistry improved with ursodeoxycholic acid, cessation of TPN and CMV resolution. She was discharged home at 7 months. Case 2: A male infant of non-consanguinous Filipino parents was born at 25 4/7 weeks. He had a patent ductus arteriosis and solitary renal cyst but no dysmorphisms or other congenital abnormalities. He required TPN. Intractable pulmonary hypertension necessitated prolonged ventilation. Cholestasis was identified at 4 weeks. Stools were initially pale. HIDA scan was non-excretory. Liver biopsy: giant cell transformation, mild portal fibrosis, no bile duct proliferation. Stools later became pigmented. A jaundice gene chip (EGL) found no mutations of familial intrahepatic cholestasis (PFIC). Kabuki syndrome was diagnosed at 4 months on chromosome array. Peak liver biochemistry: conjugated bilirubin 512umol/L, AST 731U/L, ALT 345 U/L, ALP 891U/L, GGT 65U/L. Repeat liver biopsy at 3 months: extensive giant cell transformation. EM: canaliculi with markedly reduced stubby microvilli, with finely granular to filamentous material suggesting BSEP deficiency (PFIC type 2). He died at 5 months from pulmonary hypertension. These are the first reported cases of Kabuki syndrome with low-GGT neonatal cholestasis. KMT2D gene mutations should be considered on the short list of genetic disorders causing low-GGT cholestasis. We hypothesize that in Kabuki syndrome, KMT2D gene mutations modify lysine methytransferase activity and impair FXR expression of target gene products including BSEP, leading to phenotypic PFIC type 2 disorders. Kabuki syndrome gene mutations should be included in next generation jaundice gene chip panels for neonatal cholestasis. None

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.