Table 3.

Monogenic Disorders Associated with Complex Congenital Diaphragmatic Hernia of Interest in the Differential Diagnosis of Fryns Syndrome

Gene(s)Differential DisorderMOICDH 1Other Characteristic Features
GPC3
GPC4 2		Simpson-Golabi-Behmel syndrome type 1 (SGBS1)XLRare
  • Overgrowth (pre- & postnatal), macrocephaly, dysmorphic features (coarse facies, macrostomia, wide-set eyes, palatal abnormalities), polydactyly, syndactyly, CHD & mild-to-severe ID ± structural brain anomalies
  • Overgrowth, skeletal anomalies, & tumors distinguish SGBS1 from Fryns syndrome. 3
EFNB1 Craniofrontonasal syndrome (CFNS) (OMIM 304110)XLRare (can occur in both males & females w/CFNS)Coronal synostosis, facial anomalies (wide-set eyes, wide nasal tip), & skeletal anomalies
PORCN Focal dermal hypoplasia (Goltz syndrome)XLRareLinear skin pigmentation, fat herniation, eye anomalies incl microphthalmia, small teeth, digital anomalies
BRD4
HDAC8
NIPBL 4
RAD21
SMC1A
SMC3		Cornelia de Lange syndrome (CdLS)AD
XL		RareFacial anomalies (high-arched &/or joined eyebrows, long eyelashes, short nose w/anteverted nares, small & widely spaced teeth), microcephaly, growth restriction, hirsutism, upper-limb reduction defects, ID, autistic features, self-destructive behavior
WT1 WT1 disorder (incl Denys-Drash syndrome, Frasier syndrome, Meacham syndrome) 5ADRareUrogenital anomalies, Wilms tumor, nephropathy, glomerulopathy, disorders of sexual development
FBN1 Marfan syndrome ADRareMusculoskeletal, cardiac, & ocular defects; diaphragmatic eventration & hernia can be assoc w/early-onset Marfan syndrome. 6
NR2F2 Congenital heart defects, multiple types, 4 (OMIM 615779)ADVariableFryns syndrome-like craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rockerbottom feet, single umbilical artery
LRP2 Donnai-Barrow syndrome ARCore featureFacial anomalies (wide-set eyes, enlarged anterior fontanelle); high myopia, retinal detachment, progressive vision loss, iris coloboma, sensorineural deafness; agenesis of corpus callosum; omphalocele; ID
RARB
STRA6 		Matthew-Wood syndrome (PDAC syndrome; syndromic microphthalmia) (OMIM 615524, 601186)AR
AD		Core
  • Micro-/anophthalmia, pulmonary agenesis or hypoplasia, CHD, genitourinary anomalies
  • Matthew-Wood syndrome is not assoc w/small nails or small digits.

AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHD = congenital heart defect; ID = intellectual disability; MOI = mode of inheritance; PDAC = pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, & cardiac defect; XL = X-linked

1.
2.

SGBS1 is caused by a pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4.

3.

Individuals with SGBS are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma.

4.

CDH occurring in CdLS is typically associated with pathogenic variants in NIPBL [Yu et al 2020].

5.

Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant.

6.

From: Fryns Syndrome

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.