Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome

doi:10.1067/mpd.2003.148

The Journal of Pediatrics

Volume 142, Issue 4, April 2003, Pages 441-447

https://doi.org/10.1067/mpd.2003.148 Get rights and content

Abstract

Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. A locus, LCS1, has recently been mapped to chromosome 15q in a Norwegian kindred. In a consanguine Serbian Romani family with a neonate who had a combination of lymphedema and cholestasis with features atypical for Norwegian LCS, haplotype and linkage analysis of markers spanning the LCS1 region argue that a second LCS locus may exist. The infant may represent an instance of a previously undescribed lymphedema-cholestasis syndrome. (J Pediatr 2003;142:441-7 )

Section snippets

Case report

Lymphedema of the feet was present at birth in a boy (Fig 1) born at 39 weeks' gestation to Serbian Romani parents who were third cousins.

. Patient, 4 weeks of age. Note striking pedal lymphedema.

There was no family history of hereditary lymphedema or liver disease. No hypoproteinemia was found in the first week of life. Cardiac imaging studies did not show evidence for right heart insufficiency, any other congenital cardiac disease, or any vascular abnormality.

Jaundice was noted at age 3 days;

Methods

Samples of the explanted liver of the proband were fixed in formalin and processed into paraffin; sections were cut and stained by using standard techniques as well as immunostained (Streptavidin-biotin immunoperoxidase) for cytokeratin 7 (Dako, Vienna) and the arterial and venous endothelial antigen cd34 (Serotec, Oxford, UK). Immunostaining for the lymphatic endothelial antigen podoplanin was performed with the use of a polyclonal rabbit antihuman antibody.¹⁰

DNA was isolated from circulating

Results

Marked cholestasis and extensive giant cell transformation of hepatocytes were found in the explanted liver, without significant portal tract fibrosis (Fig 4, A and B ).

. Histology of explanted liver. A, Low magnification view. Severe hepatitis with extensive intra-acinar collapse dividing the parenchyma into small islands of markedly pleomorphic hepatocytes including prominent multinucleated giant cells. There is a moderate mixed inflammatory cell infiltration and a severe panacinar cholestasis

Discussion

LCS (Aagenaes syndrome) is the only reported form of hereditary lymphedema associated with cholestasis. LCS was diagnosed in our patient, based on clinical findings of lymphedema associated with neonatal cholestasis and persisting after liver transplantation. No dysmorphism or congenital malformation other than pedal edema was found. Absent in particular were webbed neck, distichiasis, and ptosis, which might suggest a mutation in the fork head family transcription factor gene (FOXC2;

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^*: Supported in part by a National Institutes of Health grant (to L. B., R01-DK58214).

^**: Reprint requests: Thomas Müller, MD, Department of Pediatrics, University Hospital Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: [email protected]

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Clinical and Laboratory ObservationsEvidence for genetic heterogeneity in lymphedema-cholestasis syndrome*,**

Abstract

Section snippets

Case report

Methods

Results

Discussion

J Pediatr

Am J Hum Genet

Am J Pathol

Am J Hum Genet

Am J Hum Genet

Hereditary recurrent intrahepatic cholestasis from birth

Arch Dis Child

Lymphoedema in hereditary recurrent cholestasis from birth

Arch Dis Child

Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasis-lymphoedema syndrome): new cases and follow-up from infancy to adult age

Scand J Gastroenterol

Aagenaes's syndrome in an Italian child

Acta Paediatr Scand

Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome)

J Med Genet

Two cases of Aagenaes syndrome with different clinical courses [Dwa przypadki zespolu Aagenaesa o odmiennym przebiegu klinicznym]

Hepatol Polska

Clinical and Laboratory Observations
Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome*,**