Fryns syndrome without diaphragmatic hernia, DOOR syndrome or Fryns‐like syndrome? Report on patients from Indian Ocean islands

Abstract

We report on six patients (five unpublished patients) from the Indian Ocean islands, with coarse face, cleft lip or palate, eye anomalies, brachytelephalangy, nail hypoplasia, various malformations (genitourinary or cerebral), abnormal electroencephalograms with impaired neurological examination and lethal outcome. Massive polyhydramnios was noted in the third trimester of pregnancy and neonatal growth was normal or excessive. The combination of the features is consistent with the diagnosis of Fryns syndrome (FS) without congenital diaphragmatic hernia. Besides chromosomal aberrations and microdeletion syndrome, differential diagnoses include conditions overlapping with FS such as Simpson-Golabi-Behmel, and conditions with hypoplasia/absence of the distal phalanges such as DOOR syndrome, Schinzel-Giedion syndrome, and Rudiger syndrome.

Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome

“…In this report, using exome sequencing we have detected a 5.07 kb homozygous intragenic deletion in PIGN in two siblings who had been previously reported in a series of six patients clinically diagnosed as FS or Fryns-like syndrome [8]. The homozygous deletion was also identified in two new unrelated patients having a severe MCA condition with extreme brachytelephalangia.…”

“…They were previously published in a series of six patients from Indian Ocean islands having a MCA syndrome with hypoplasia/absence of the distal phalanges. Their shared condition was thought to represent a distinctive entity, overlapping FS, DOORS, or Schinzel-Giedion syndromes [8].…”

“…A clinical description of patients 1 and 2 (individuals II-1 and II-2, respectively, of family 1 in Fig. 1) has been previously published (patients 1 and 2, respectively, in Alessandri et al [8]) and the key features are reproduced here as follows:…”

“…Genetic heterogeneity was suspected by McInerney-Leo et al [6], as two FS cases were negative for PIGN variants. We performed whole-exome sequencing of one patient from La Réunion Island with a clinical diagnosis of FS [8] and of one FS patient with consanguineous parents of North African origin. A homozygous loss of function PIGN allele (an intragenic deletion or a frameshift) was identified in each case.…”

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

“…Prenatal manifestations of GPIBDsincluded increased nuchal translucency (NT), polyhydramnios, cleft lip/palate, congenital heart defects (CHDs), congenital diaphragmatic hernia (CDH), omphalocele, genitourinary abnormalities and short limbs. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Interestingly, based on these prenatal findings, it has been proposed that variants in PIGN, PIGV and PIGA could be associated with Fryns or Fryns-like phenotype, a condition for which a molecular diagnosis has long remained puzzling. 13,14,16,17,28,29,33 Here we report on three fetuses, from two different families, with MCA and homozygous variants in PIGW, contributing to expanding the current knowledge about the prenatal manifestations of GPIBDs.…”