Congenital Imprinting Diseases: Aetiology, Pre- and Perinatal Manifestations, Diagnosis and Care of Affected Families and Pregnancies

Abstract

Congenital Imprinting Disorders (ImpDis) are caused by abnormal expression of parentally imprinted genes. They are characterized by disturbances of imprinting marks which are a specific type of epigenetic signatures and occur either sporadic or familial. So far, twelve ImpDis have been identified, eight of them manifest prenatally or in the neonate period. With exception of abdominal wall defects, ImpDis are rarely associated with major malformations, but predominant early manifestations are disturbed pre- and/or postnatal growth, muscular hypotonia, neonatal feeding difficulties and metabolic/hormonal dysfunction. With few exceptions prenatal clinical features of ImpDis are unspecific and manifest only in the late second or third trimester. In some ImpDis, behavioural, developmental, and neurological symptoms might emerge, and in single ImpDis there is a higher risk of cancer in childhood.

Prenatal diagnosis plays a crucial role in appropriate pregnancy management and initial care of the newborn, which in turn has positive impact on the life-long outcome of the patient. Furthermore, the diagnosis of ImpDis is relevant for the prevention of pregnancy risks such as preeclampsia and possible reproductive problems in future pregnancies and other family members.

Genetic analysis is not straightforward, and imprinting disturbances may escape both DNA sequencing analysis and (molecular-)cytogenetic diagnostics. After introducing the topic with a case report, this review focuses on the recognition of ImpDis including maternal and family history, exogeneous and genetic risk factors, fetal imaging, and genetic findings as well as interdisciplinary care and treatment approaches in the management and decision making of affected families and pregnancies.

Zusammenfassung

Angeborene Imprinting-Erkrankungen (ImpDis) werden durch eine aberrante Expression elterlich geprägter Gene verursacht. Sie zeichnen sich durch Störungen der Imprinting-Markierungen aus, einer spezifischen Art von epigenetischen Signaturen, und treten entweder sporadisch oder als familiäre Störung auf. Bislang wurden 12 ImpDis identifiziert, davon manifestieren sich 8 bereits pränatal oder in der perinatalen Periode. Mit Ausnahme von Bauchwanddefekten sind ImpDis selten mit pränatal deutlichen Missbildungen verbunden. Zu den häufigsten frühen Manifestationen zählen pränatale und/oder postnatale Wachstumsstörungen, Muskelhypotonie, neonatale Trinkschwäche und metabolische/hormonelle Dysfunktion. Mit wenigen Ausnahmen sind die pränatalen klinischen Merkmale von ImpDis unspezifisch und zeigen sich erst im späten 2. oder 3. Trimenon. Bei einigen ImpDis können Verhaltens-, Entwicklungs- bzw. neurologische Symptome entstehen, and einzelne ImpDis sind mit einem höheren Risiko verbunden, im Kindheitsalter Krebs zu entwickeln.

Die pränatale Diagnose spielt für ein angemessenes Management der Schwangerschaft und der Erstversorgung des Neugeborenen eine wichtige Rolle, was wiederum positive Auswirkungen auf das lebenslängliche Outcome des Patienten haben kann. Hinzu kommt, dass eine ImpDis-Diagnose für die Vorbeugung von Schwangerschaftsrisiken wie Präeklampsie und mögliche Fertilitätsprobleme bei zukünftigen Schwangerschaften sowie für andere Familienmitglieder relevant ist.

Die genetische Analyse im Hinblick auf ImpDis ist komplex, und Imprinting-Störungen können sowohl der DNA-Sequenzierung als auch der (molekular-)zytogenetischen Diagnostik entgehen. Nach einer Einführung in das Thema anhand eines Fallbeispiels liegt der Schwerpunkt dieses Übersichtsartikels auf der Erkennung von ImpDis und beinhaltet auch die mütterliche und Familienanamnese, exogene und genetische Risikofaktoren, die fetale Bildgebung und die genetischen Befunde sowie die interdisziplinäre Versorgung und Behandlungskonzepte für das Management und die Entscheidungsfindung von betroffenen Familien und bei Schwangerschaften.

Keywords

imprinting disorders - fetal imaging - genetic diagnosis - genetic counselling

Schlüsselwörter

Imprinting-Erkrankungen - fetale Bildgebung - genetische Diagnose - genetische Beratung

Publication History

Received: 20 January 2025

Accepted after revision: 15 March 2025

Article published online:
28 April 2025

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