Table 1.

Congenital Diaphragmatic Hernia: Monogenic Causes and Distinguishing Clinical Features

Gene(s) 1SyndromeMOIOccurrence of CDH in Persons w/the SyndromeDistinguishing Clinical Features
LRP2 Donnai-Barrow syndrome AR+++
  • Enlarged anterior fontanelle, agenesis of the corpus callosum, hypertelorism, retinal anomalies, omphalocele or umbilical hernia
  • Sensorineural hearing loss, myopia, ID
  • Characteristic pattern of low-molecular-weight proteinuria
LTBP4 LTBP4-related cutis laxa AR+++Loose redundant skin, pulmonary emphysema, GI & bladder diverticula
MYRF MYRF-related cardiac urogenital syndrome AD+++Congenital heart defects, GU defects
RARB
STRA6 		Microphthalmia, syndromic
(OMIM 615524; 601186)		AR+++Micro-/anophthalmia, pulmonary agenesis or hypoplasia, cardiac malformations, GU anomalies
RLIM Tonne-Kalscheuer syndrome (OMIM 300978)XL+++
  • ID, behavioral difficulties
  • GU malformations, distal digital hypoplasia
COX7B
HCCS
NDUFB11 		Microphthalmia with linear skin defects syndrome XL++
  • Microphthalmia, sclerocornea, linear dermal hypoplasia, brain, cardiac, & GU anomalies, nail dystrophy
  • Hearing impairment
NR2F2 Congenital heart defects, multiple types, 4
(OMIM 615779)		AD++Congenital heart defects
PIGN PIGN-related Fryns syndrome 3AR+++
  • Characteristic facial appearance; short distal phalanges of fingers & toes; pulmonary hypoplasia; & assoc anomalies (polyhydramnios, cloudy corneas &/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, &/or malformations involving brain, cardiovascular system, GI system, &/or genitalia)
  • Survival beyond neonatal period is rare.
SLC2A10 Arterial tortuosity syndrome AR++Arterial tortuosity, stenosis, & aneurysms, joint laxity, hyperextensible skin
ZFPM2 Diaphragmatic hernia type 3 (OMIM 610187)AD++Congenital heart defects, gonadal dysgenesis, ambiguous genitalia
ARID1A
ARID1B
SMARCA4
SMARCB1
SMARCE1
SOX11 		Coffin-Siris syndrome AD+
  • Hypoplasia/absence of nail/phalanx of 5th digit (& occasionally of additional digits), scalp hypotrichosis, body hypertrichosis, facial dysmorphology (coarse face, wide mouth, full lips), brain & cardiac anomalies
  • Growth restriction
  • ID
Imprinting
defect at
11p15.5
CDKN1C		 Beckwith-Wiedemann syndrome See footnote 2.+
  • Prenatal &/or postnatal overgrowth, macroglossia, visceromegaly, hemihypertrophy
  • Abdominal wall defects, earlobe creases or pits behind the upper ear
  • Embryonal tumors
CHD7 CHARGE syndrome (See CHD7 Disorder.)AD+
  • Coloboma, ear anomalies, cranial nerve deficits, choanal atresia or stenosis, oral facial clefts, cardiac malformations, GU anomalies, tracheoesophageal atresia
  • Growth deficiency
COL3A1 Vascular Ehlers-Danlos syndrome AD+
  • Arterial & visceral fragility & rupture
  • Thin translucent skin, micrognathia, narrow nose, thin vermillion of lip, prominent eyes, acrogeria, joint hypermobility
DLL3
HES7
LFNG
MESP2
RIPPLY2
TBX6 		Spondylocostal dysostosis AR+Hemivertebrae, vertebral fusion, scoliosis, rib anomalies, short stature, cleft palate, digital anomalies, & renal anomalies
EFNB1 Craniofrontonasal syndrome (OMIM 304110)XL+Hypertelorism, broad or bifid nose, midface hypoplasia, craniosynostosis, digital anomalies
FBN1 Marfan syndrome AD+Connective tissue dysplasia characterized by tall stature, long limbs, subluxation of the lens, dilatation of the ascending aorta
FGFR2 Apert syndrome (See FGFR Craniosynostosis Syndromes Overview.)AD+
  • Craniosynostosis, mid-face hypoplasia, hypertelorism, fusion of cervical vertebrae, soft tissue & bony syndactyly of hands & feet
  • ID
FRAS1
FREM2 		Fraser syndrome (OMIM 219000)AR+Cryptophthalmos; syndactyly; GU, ear, and laryngeal malformations
GATA4 Congenital diaphragmatic hernia & heart defects [Yu et al 2013]AD+Congenital heart defects
GATA6 Heart defects, congenital & other congenital anomalies (OMIM 600001)AD+
  • Congenital heart defects, pancreatic agenesis, gallbladder agenesis
  • DD
GPC3 Simpson-Golabi-Behmel syndrome type 1 XL+
  • Macrosomia, macrocephaly, hypertelorism, umbilical hernia, omphalocele, ocular & renal anomalies
  • Embryonal tumors
  • ID
KMT2D Kabuki syndrome AD+
  • Long palpebral fissures, eversion of lower eyelids, arched/discontinuous eyebrows w/lateral thinning, prominent ears, oral clefts, fetal finger pads, short 5th finger, cardiovascular malformations
  • Postnatal growth deficiency
  • Mild-to-moderate ID
KDM6A XL
NIPBL
RAD21
SMC3 		Cornelia de Lange syndrome AD+
  • Microcephaly, synophrys, arched eyebrows, long eyelashes, small upturned nose, growth deficiency, hirsutism, upper limb anomalies
  • ID
HDAC8
SMC1A 		XL
POGZ White-Sutton syndrome AD+
  • DD, autism, ID
  • Hypotonia, facial dysmorphism, visual impairment
PORCN Focal dermal hypoplasia XL+
  • Asymmetry of the face, trunk, & extremities; skin atrophy w/fat herniation, hyper- & hypopigmentation, mucous & perioral papillomas, digit anomalies, dental anomalies, coloboma, microphthalmia; osteopathia striata
  • Mild ID
  • High frequency of male lethality
WT1 Denys-Drash syndrome (See WT1 Disorder.)AD+
  • GU anomalies, typically undermasculinized 46,XY individuals, diffuse mesangial sclerosis
  • Wilms tumor
  • Early-onset renal failure
Meacham syndrome (See WT1 Disorder.)
  • 46,XY males, undervirilization of external male genitalia, ambiguous or female external genitalia, retained müllerian structures w/double vagina
  • Pulmonary hypoplasia, complex cardiac malformations

AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; GU = genitourinary; MOI = mode of inheritance; XL = X-linked; DD = developmental delay; ID = intellectual disability

+++ = CDH is considered a core feature in this syndrome. For extensively reported syndromes, CDH is a common finding (i.e., >40%).

++ = CDH is a variable feature of this syndrome. For extensively reported syndromes, CDH is a less common finding (i.e., ~10%-40%). For less extensively characterized syndromes, multiple case reports of CDH are present in the published literature.

+ = CDH is a rare feature of this syndrome. For extensively reported syndromes (e.g., trisomy 21), many case reports of CDH are present in the literature, though the overall incidence of CDH in this syndrome is estimated at <10%. For less extensively characterized syndromes, few case reports are present in the literature; however, it is not generally considered to be a component of the syndrome.

1.

Genes are listed alphabetically

2.

The majority of Beckwith-Wiedemann syndrome (BWS) is caused by imprinting defects or uniparental disomy of 11p15.5 and is simplex (i.e., a single occurrence in a family). In a small number of affected individuals, BWS is caused by a maternally inherited pathogenic variant in CDKN1C.

3.

Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals clinically diagnosed with Fryns syndrome have not had PIGN pathogenic variants identified. However, the number of individuals meeting the clinical diagnostic criteria for Fryns syndrome with negative testing for PIGN variants is unknown (see Fryns Syndrome).

From: Congenital Diaphragmatic Hernia Overview

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