Fryns syndrome

Definition

Fryn syndrome is a genetic disorder associated with X-linked chromosome that causes mutation in genes. The specific gene responsible for this condition is yet unknown, as the X-linked Chromosome has more than 1000 genes. It is an Autosomal Recessive Character that can run in families or may be hereditary. It is diagnosed very late beyond the neonatal period; in some cases, it may be Fatal in the early neonatal stage and some defects lead to miscarriage. Few patients have survived beyond the neonatal period after successful operation of defects that were possible to replace or bring some anatomical changes in the organs affected. Example -Cleft Palate. It was first reported by Fryns et al,1979 hence, the name Fryns Syndrome.

Clinical features

Multiple anomalies were observed in pregnancy as Heart Palpitation of the Fetus and Growth rate were monitored even though the prognosis was not easy after birth some defects observed were further evaluated with the help of a test to confirm the syndrome. Below are the feature observed till now in cases reported in various regions, facial appearance eyes are prominent and wide, large mouth with tiny jaw, fingers deformity, mild mental retardation, malformation in urogenital region, abnormality in diaphragm, most cases showed defects in the heart leading to other anomalies as blood flow was altered.

Cardiac anomalies and common heart defects

Diaphragmatic Defects with multiple congenital anomalies were commonly reported with confirmed clinically observed features. The anomalies were characterized as CVM i.e., Cardiovascular Malformation, CDH, Congenital Diaphragmatic Hernia and CHD Congenital Heart Disease. These anomalies were confirmed after the clinical observations and further tests like ECG, Chest X-ray and CT SCAN were done to support the evidence. It is a genetic disorder hence some Genetic testing like Karyogamy, Whole Genome Sequencing, EXOME genome sequencing, etc.

Background

Malformation of internal organs such as ruptured veins and arteries, pulmonary hypoplasia lungs poorly developed causing breathing difficulty, neonatal lethal defects as intestinal loop, thorax cavity shortened, oesophagal lesions, erect nose, underdeveloped dactyl conditions, pulmonary stenosis.

Ventricular, articular or aorta defects are seen in children leading to an opening in the upper and lower chambers. Rare survival patients though some that survive show delays in development as the defects cause multiple organ dysfunctioning.

Description

Cardiovascular malformation CVM, septal defects like obstruction in valves and opening leading to over circulation, some patients with such defects can be operated by open heart surgery replacing the valves’ cause deformation in central nervous system, skeletal system and genital system. Prognosis is very difficult in the preliminary stage.

Congenital diaphragmatic hernia CDH is relatable to CVM cardiovascular malformation defects in the sterna and crural portions of diaphragm causing about 7% of diaphragmatic hernia. Right-sided hernia is reported more but not necessarily seen in all patients hence can be bilateral hernia too. Defects are asymptomatic and diagnosed after neonatal period.

Congenital heart disease CHD, CVM and CDH are a part of heart disease but do not confirm FRYNS syndrome only with a few abnormalities associated with congenital heart disease. Phenotypic variations differ from patient to patient considering the family history taken while diagnosis and the clinical test evidence. CHD congenital heart disease in FRYN syndrome has the following observations commonly reported to date, Chest nipples wide and hypoplastic, undescended testicles, overlapping of fallopian tubes, lesions in chest cavity along with cardio system and thoracic cavity. Ventricular hypertrophy, Brachyphalangy i.e. more the 1 or 2 phalanges on fingers.

Right side of the internal chest cavity has more anomalies than the left side, as the left region causes pulmonary hypoplasia though the left-sided anomaly is Fatal and no surgical methods or defects improvement can survive the patient.

Tetralogy of fallot (TOF)

TOF, known as congenital heart disease caused due to chromosomal abnormality hence it is linked up with FRYN SYNDROME as the symptoms are co-related. All 4 chambers of heart are marred in TOF leading to various coronary defects, commonly, Ventricular septal defects, Aorta deformity and presence of lesions narrowing the aorta pipe, right ventricular outflow tract also known as RVOTO causing insufficient blood flow and oxygen to various organelles ultimately leading to Cyanosis and rapid deterioration. Alteration is seen in both the artery and veins limiting pulmonary circulation resulting in heart failure. RVOTO increases cyanosis resulting in desaturation. Aorta malfunctioning condition is lethal as the valve blood flows on one side of either artery or vein leads to air trapping, causing tracheobronchomalacia collapse of the airway. Few conditions under clinical observations are thickening of valves rather than. normal, overriding of aorta, pulmonary stenosis, ventricular and articular lesions and hypoplastic region leading to hypertrophy Not all FRYN syndrome has TOF but causative genes are yet unknown specific to TOF. Rest other mutations can be with variable anomalies observed from patients.

Case series

A case report was published in May 2024 under FRYN syndrome in the PubMed database about the prenatal diagnosis with the help of 2 novel splice variants in PIGN gene. Evidence was based clinically on the whole genome sequence done under experts identifying 2 splicing causing mutation in exon 29 & 30 base pair and intron 12 via RNA sequencing.

PIGN gene and Fryns syndrome (FS)

It is observed that mutation in PIGN gene amongst 2 to 3 % of FRYN syndromic patients. Reported study suggests Biallelic truncating variants in PIGN encoding a biosynthesis pathway cause multiple anomalies along with cardiac defects.

Patients with FS but no CDH congenital heart defects showed loss of PIGN alleles. Severity of GPI deficiency i.e., glycosylphosphatidylinositol leading disruption in GPI anchor pathway, associated with recessive PIGN variants ranging from extreme Fryn syndrome anomalies.

CDH in FRYN syndrome was responsible for early death in neonatal., without CDH the survival rate was high extending beyond neonatal period with developmental delays. FS associated failure of GPI pathway causing alkaline phosphatase to cell surface resulting to hyperphosphate with mental retardation syndrome called Mabry syndrome. No PIGN was found associated directly with this syndrome.

PIGN (phosphatidylinositol glycan anchor biosynthesis class N), case was reported usually in same family or siblings’ fitting an example of recessive inheritance model hence it supports the factor recessive mutation in PIGN.

Case reported and their features observed

• A case of neonate born with facial and limb deformity after clinically evaluation had Fryn syndrome as well as Edward syndrome, A rare case from India reported in the,2022 though the child could not be survived and we hope there will be more research and possible advanced test to detect such anomaly before birth
• An Anomaly led to other findings of syndrome, in 1991 a case study suggests a child born with Pelger-Huet anomaly, condition in which white blood cells have an unusual shape then normal causing effect on body organs after further evaluation the child had CHD and CVM and few internal anomaly correlating with Fryn syndrome
• A male born at 23 weeks of gestation died immediately after birth. Autopsy showed pulmonary hypoplasia. He had neck webbing i.e., skin folded at the side of the neck, hypoplasia of the pharyngeal, urogenital organs had malformation
• A female infant with CDH was delivered at 33 weeks of gestation and had poor respiratory status. Examination showed coarse facial appearance with a wide forehead crease, a flat nose bridge, dysplasia seen on ears and lips. Broad chest and widened nipples. Dactyl condition on finger and toes, nail was outgrown of few fingers
• A female delivered a premature child at 31 weeks gestation but the infant died in the next hour. An autopsy, findings revealed right hypoplasia and CDH, atresia of oesophageal region, i.e. abnormal opening at duodenum, atrial septal defect, hyperplasia of pancreas, and a two-vessel umbilical cord. Malformed ears in round shape and face appeared small compared to facial organs

Results

The exact FRYN syndrome cases are unknown though more than 200 cases are observed out of which 35% are CDH, 50% are fatal in neonatal, few died during miscarriage and some survived till 1 year with intense care. The Remaining 15% were either born with deformity or malformation in lungs or heart and survived after surgical repairs and monitoring.

Summary

• Prenatal tests should be mandatory along with parents’ heredity counselling or family history to be discussed
• Awareness about such syndrome with examples of earlier patients to be shown to parents so that they do all the necessary tests
• Routine health check-ups in terms of cardio and lungs must be mandatory
• Genetic testing like Karyogamy or Sequencing of genes to be done before expecting a child
• Prevention in dietary or medicines prescribed by doctors during pregnancy must be followed after any detection
• Fetal pulses test and any possible test like USG must be considered very seriously