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Fryns Syndrome


Introduction

First described in 1979, Fryns syndrome is a rare autosomal recessive disorder characterized by diaphragmatic defects, dysmorphic facial features, distal limb hypoplasia, pulmonary hypoplasia, and associated anomalies of other major organ systems. To date the diagnosis is made solely by clinical criteria, as only one candidate gene has been identified through whole exome sequencing. Although Fryns syndrome was initially thought to be uniformly lethal, there are now multiple reports of survivors exhibiting varying phenotypes. While prenatal ultrasound (US) may identify features suggestive of Fryns syndrome, postnatal confirmation is required for diagnosis.

Disorder

Definition

Diagnostic guidelines have most recently been reviewed and revised by Lin et al. in 2005 and include six major clinical features :

  • 1.

    diaphragmatic defect (hernia, eventration, hypoplasia, agenesis)

  • 2.

    distal digital hypoplasia (nails and/or phalanges)

  • 3.

    significant pulmonary hypoplasia

  • 4.

    characteristic facial appearance (coarse face, hypertelorism, broad and flat nasal bridge, long philtrum, low-set and poorly formed ears, tented upper lip with macrostomia, micrognathia)

  • 5.

    associated anomalies (polyhydramnios, cloudy cornea or microphthalmia, orofacial cleft, brain malformation, cardiovascular malformation, renal dysplasia, gastrointestinal malformation, genitourinary malformation)

  • 6.

    sibling affected with Fryns syndrome

Patients are then further categorized into one of the following three subtypes based on the aforementioned clinical criteria:

  • 1.

    Narrowly defined: four of six clinical features.

  • 2.

    Broadly defined: three of six clinical features.

  • 3.

    Atypical.

Prevalence and Epidemiology

Over 110 cases of Fryns syndrome have been reported since its initial description in 1979, with an estimated prevalence of 7 : 100,000 live births. It is the most common syndrome associated with congenital diaphragmatic hernia, with a risk association ranging from 1%–10%.

Etiology and Pathophysiology

Fryns syndrome is inherited in an autosomal recessive pattern and should be considered in any patient with a congenital diaphragmatic hernia and a prior affected family member. Although the molecular mechanism has yet to be elucidated, multiple chromosome aberrations, such as microdeletions on chromosomes 1, 8, and 15; partial trisomy 22; and mosaic tetrasomy 12p, have been associated with a similar phenotype. It is recommended that these chromosome abnormalities be excluded by karyotype or chromosome microarray before assigning the diagnosis of Fryns syndrome.

The pathogenesis of Fryns syndrome is not well understood; however, abnormal neural crest cell migration may play a role. In addition, with the clinical implementation of whole exome sequencing, novel deleterious mutations in the PIGN gene have been reported in multiple individuals with a clinical diagnosis of Fryns syndrome. PIGN is one of a number of genes that codes for the production of glycosylphosphatidylinositol (GPI), which functions by attaching various proteins to the lipid layer of cell membranes. GPIs are involved in many cellular processes, some of which function in developmental pathway signaling. Mutations in this gene have also been reported in other individuals with multiple congenital anomalies. Additional research is needed to delineate the association between PIGN and Fryns syndrome as well as to determine other genes that may be implicated in this condition.

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