Fryns syndrome: A rare case report with review of ...

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Case Report

Fryns syndrome: A rare case report with review of literature Tanima Dwivedi, Bhagyashri Hungund Department of Pathology, KLE University’s Jawaharlal Nehru Medical College, Belagavi, Karnataka, India

ABSTRACT Fryns syndrome is a rare multiple congenital anomaly syndrome with incidence of 0.7-1 in 10,000 births. Characteristic features of this syndrome are congenital diaphragmatic hernia, lung hypoplasia, unusual facial features, limb defects and parental consanguinity. Here we report a case of Fryns syndrome of consanguineous parents at the gestation age of 27 week old. Mother presented to department of obstetrics and gynaecology with inability to perceive fetal movements. Ultasonography revealed polyhydramnios, intrauterine growth retardation, and congenital anomaly of diaphragm and absence of fetal heart sound. Based on ultrasound findings, clinical diagnosis of congenital diaphragmatic hernia was made for which therapeutic abortion was performed and a still born fetus was delivered which was sent for post mortem study. On autopsy, diagnosis of Fryns syndrome was made. Key words: Congenital diaphragmatic hernia, fryns syndrome, lung hypoplasia, parental consanguinity

INTRODUCTION

CASE REPORT

Fryns syndrome is a rare autosomal recessive disorder. It was first described by Fryns et al. in 1979. The incidence of Fryns syndrome is 0.7–1 in 10000 births.[1] Congenital diaphragmatic hernia (CDH) is a cardinal feature of this syndrome. Other features of this syndrome include pulmonary hypoplasia, characteristic facial appearance, distal digital hypoplasia, and parental consanguinity. The associated systemic anomalies are renal dysplasia, renal cortical cysts, malformations involving the brain, cardiovascular system, gastrointestinal system, and genitalia.[1]

A 25‑year‑old primigravida in her 27 th week of gestation presented to obstetrics department with an inability to perceive fetal movements since 1 day. History of consanguineous marriage was present. Antenatal ultrasound scan performed revealed polyhydramnios, intrauterine growth retardation, congenital anomaly of diaphragm, and absence of fetal heart sound. Based on ultrasound findings, clinical diagnosis of congenital diaphragmatic hernia was made, for which therapeutic abortion was performed and a still born fetus was delivered; the fetus was sent for postmortem study.

Here, we present a case of Fryns syndrome because of its rarity to describe its pathological features and to discuss the literature of this rare entity.

Autopsy findings A fetus with attached umbilical cord along with placenta was received for autopsy study. Placenta weighed 75 g and measured 12 × 5.5 × 3 cm; the fetus weighed 200 g. Umbilical cord measured 20 cm

Address for correspondence: Dr. Tanima Dwivedi, Emergency Laboratory, Institute of Human Behaviour and Allied Sciences, New Delhi, India. E‑mail: [email protected] Access this article online Quick Response Code: Website:

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DOI:

How to cite this article: Dwivedi T, Hungund B. Fryns syndrome: A rare case report with review of literature. J NTR Univ Health Sci 2018;7:147-53.

10.4103/JDRNTRUHS.JDRNTRUHS_121_16

© 2018 Journal of Dr. NTR University of Health Sciences | Published by Wolters Kluwer - Medknow

147


Dwivedi and Hungund: Fryns syndrome

and showed only two vessels. Head circumference, chest circumference, and abdominal girth were 17, 15, and 13, cm respectively. Crown rump and crown heel length was 16.5 and 28.5 cm, respectively.

ambiguous genital organ, diaphragmatic hernia, and pulmonary hypoplasia, a diagnosis of Fryns syndrome was given. However, cytogenetics studies were not performed.

External examination showed microcephaly, widely spaced protuberant eyes, broad and depressed nasal bridge, micrognathia, extra space between the nose and upper lip, large mouth, and, low set ears, and short forearm with camptodactyly. External genitalia were ambiguous [Figure 1].

DISCUSSION

On dissection, it was found that the left part of the diaphragm was deficient, and the left lobe of the liver, spleen, and coils of the intestine had protruded through this deficiency in the thoracic cavity. Heart was pushed to the right side of the thoracic cavity, and the left lung was hypoplastic. The left lung weighed 2 g and measured 1.3 × 1× 0.3 cm; the right lung weighed 7 g and measured 3 × 2× 0.5 cm. Gross morphology of the heart, liver, spleen, and right and left kidneys appeared normal. Internally, female reproductive organs were found and appeared normal [Figure 1]. Microscopic examination revealed hypoplasia of the left lung. The microscopic features of the heart, liver, spleen, kidneys, and reproductive organs (uterus) showed normal features without any obvious pathology. Based on above findings, i.e., dysmorphic facial features, hypoplasia of arm with camptodactyly,

a

c

Lin et al. described the six diagnostic criteria for Fryns syndrome which include[1] 1. Parental consanguinity 2. Diaphragmatic defect (which is a cardinal features) 3. Pulmonary hypoplasia 4. Characteristic facial appearance (coarse facies, ocular hypertelorism, microphthalmia, low‑set, poorly formed ears, a broad and flat nasal bridge, thick nasal tip with anteverted nares, long philtrum, tented upper lip, macrostomia, and microretrognathia) 5. Distal digital hypoplasia, mainly distal limb hypoplasia that includes short and broad hands, short digits, short terminal phalanges, hypoplastic or absent nails and clinodactyly 6. Characteristic associated anomalies such as polyhydramnios, brain malformations, renal dysplasia, gastrointestinal system malformations, and genital malformations. At least 4 out of 6 features should be present for making the diagnosis of Fryns syndrome. The present case showed all the diagnostic features (parental consanguinity, congenital diaphragmatic hernia, pulmonary hypoplasia, characteristic facial appearance, distal digital hypoplasia, and genital malformations).[1]

b

d

Figure 1: (a and b) Fetus showing congenital diaphragmatic hernia (CDH) with herniation of intestine, liver into left side of thorax and left lung is hypoplastic (arrow). (c) showing CDH (part of liver intestine from defect), left hypoplastic lung(arrow), camptodactyly with umbilical cord showing two vessels. (d) showing amphigous genital (arrow) 148

Fryns syndrome is a rare multiple anomaly congenital syndrome. Its incidence is 0.7 per 10000 births. It has autosomal recessive mode of inheritance. [1] Table 1 lists studies of Fryns syndrome conducted till date.[2]

Congenital diaphragmatic hernia results from failure of complete closure of the pleuroperitoneal canal at the embryonic period of 8–10th gestational week. A total of 1.3–10% cases of Fryns syndrome have congenital diaphragmatic hernia, which is the cardinal feature for this syndrome.[3] Congenital diaphragmatic hernia occurs more often on the left hemithorax and the most common subtype is the posterolateral or Bochdalek type, which was also seen in the present

Journal of Dr. NTR University of Health Sciences | Volume 7 | Issue 2 | April-June 2018

Year

1978

1979

1983

1985

1986

1987

1987

1988

1989

1990

1991

1991

1995

1992

1995

1995

Fryns et al.

Fryns et al.

Lubinsky et al.

Meinecke and Fryns

Young et al.

Samue loff et al.

Schwyzer et al.

Moerman et al.

Ayme et al.

Cunniff et al.

Kershis nik et al.


Willems et al.

Bartsch et al.

Hanssen et al.

Riela et al.

Van Hove et al.

1

1

2

2

1

1

4

8

2

1

4

1

1

2

2

1

No of Pt

M Upto 3 years

M

M, F

M (12 days)

M, F

F

Sex

Cleft lip and palate Cloudy cornea

Abnormal face

Cleft palate, Retrognathia Micrognathia

Corneal clouding

Broad nasal bridge, Microretrognathia, Abnormal helices, Cleft palate. Cleft lip

Coarse facies, Cloudy cornea

Facies defects

Survivors tended to have less frequent DH

Without DH

DH is not a necessary feature of Fryns syndrome

Bilateral DH had been repaired on the first day of life

DH

DH

DH

DH

DH

DH

DH

Left DH

Diaphragmatic defects

TABLE 1: STUDIES DONE BY VARIOUS AUTHORS TILL DATE

Studies

Survivors tended to have milder LH

Without LH

LH

LH

LH

LH

Lung lobulation absent

Lung defects

Osteochondro dysplasia

DDH

DDH

DDH

Camptodactyly Hypoplastic nails

DDH

DDH

Limb defects

Hypoplastic optic tracts, Malformations of gyration and sulcation (around the central sulcus)

Cerebral and brainstem atrophy

Mentally retarded

Mentally retarded

Hydrocephalus Scoliosis Extranumerary vertebral bodies, 13 ribs

DWA, Corpus callosum Agenesis

DWA

DWA

Hydrocephalus, Arhinencephaly

CNS defects

Septal defects Aortic arch anomalies

VSD

+

CVS defects

Hypoplastic external genitalia Renal cysts, Urinary tract malformations Bifid or hypoplastic uterus or Immature testes

Renal cystic dysplasia

Shawl scrotum, uterus bicornis, renal cysts

Urogenital defects

Duodenal atresia, pyloric hyperplasiamalrotation of common mesentery

GIT defects

+

+

+

Consanguinity

Contd...

They described a child with all the usual features except for diaphragmatic hernia

Fetal hydrops

Polyhydramnios

Abnormalities of the diaphragm as cardinal features

Important point



149

150

2005

2005

2009

2012

2012

2013

Alessandri et al.

Lin et al.

Dentici et al.

Nirmala devi et al.

Arakeri et al.

Roy et al.

2003

Arnold et al.

2005

2000

Ramsing et al.

Slavotinek et al.

2000

Vargas et al.

2004

1998

Fryns and Moerman

Pierson et al.

Year

TABLE 1: CONTD...

Studies

1

1

2

1

112

1

77

1

5

2

1

No of Pt

M

F, Twin

M, (6 year old)

M

Twin

M

Sex

Widely spaced protuberant eyes, broad depressed nasal bridge, extra space between nose and upper lip, large mouth, small chin

Microcephaly, Low set ears, Micropnathia, Flat nasal bridge

Coarse facies, Large mouth, Retrognathia, Short neck, Corneal leukoma

Microphthalmia Cloudy cornea

Midline cleft lip, alveolar ridge, and maxillary bone, and Cleft nose Bilateral choanal atresia

Bilateral cleft lip and palate Multiple pterygias. Fetal hydrops, Cystic hygroma

coarse facial appearance

Facies defects

Congenital DH

Congenital DH

Congenital DH Narrow thorax with hypoplastic nipple

Congenital DH Narrow thorax with hypoplastic nipple

without DH

DH

DH

DH

Diaphragmatic defects

LH

LH

LH

LH

Lung defects

DDH

Both Upper and lower limb had 4 fingers

Camptodactyly, clinodactyly

DDH

DDH

Limb defects

Severe psychomotor retardation, with no verbal capacity

Left arrhinencephaly Cerebellar hypoplasia

Macrocephaly 13 ribs

Midline scalp defects

CNS defects

56 case had CVS abnormaly

CVS defect

CVS defects

Horseshoe kidney

Urogenital defects

Intestinal malrotation

Gastroschisis

GIT defects

+

Consanguinity

Contd...

Postulated a role for aberrant neural crest cell migration in certain features of the disorder

Autosomal recessive most common than the sporadic inheritance

Important point






+

No specific genetic cause responsible for Fryns syndrome has been reported. However, several chromosomal aberrations such as Mosaicism for a tandem duplication of chromosome 1q24‑q31.2, ring chromosome 15, terminal deletion of chromosome 6 q, trisomy 22, and XO karyotype have been reported in literature.[1]

camptodactyly

ears

mouth, Low set

upper lip, Large

between nose and

Extra space

Micrognathia,

nasal bridge,

and depressed

eyes, Broad

Pt: Patients, F: Female, M: Male, DH: Diaphragmatic hernia, LH: Lung hypoplasia, DDH: Distal digital hypoplasia, DWA: Dandy‑Walker Anomaly, +: Present

genital organ

Amphigous Microcephaly

forearm with

Short LH Congenital DH Our study

protuberant

Widely spaced 1

F

Diaphragmatic defects Year Studies

TABLE 1: CONTD...

No of Pt

Sex

Facies defects

Lung defects

Limb defects

CNS defects

CVS defects

Urogenital defects

GIT defects

Consanguinity

Important point

case. [3] However, few authors have reported cases described as Fryns syndrome without congenital diaphragmatic hernia [Table 1].

Diagnosis of Fryns syndrome is based mostly on clinical and pathological features. Prenatal diagnosis especially by three‑dimensional ultrasonography and fetal magnetic resonance imaging with genetic studies done in the early weeks of pregnancy can be helpful in diagnosis this fatal syndrome. Genetic counseling should be considered for all those with a family history of the disease. Array comparative genomic hybridization (array CGH) can be useful in differentiating Fryns from other chromosomal condition with congenital diaphragmatic hernia.[2,4] Differential diagnosis includes various syndromes with overlapping features that need to be differentiated from Fryns syndrome, especially during autopsy for an accurate diagnosis [Table 2].[1,4] Prognosis of Fryns syndrome is usually poor and depends on malformations present. It has a high mortality rate. Patients without diaphragmatic defects have a better prognosis. Approximately 36.5% of fetuses die before 36 weeks of gestation, and 32.2% are born alive after 36 weeks but die within the first few days of life.[1] Because Fryns syndrome is autosomal recessive inheritance, autopsy study of suspected cases will assist in counseling the parents about recurrence of the disease in subsequent pregnancies and advising regular antenatal ultrasound scan, fetal magnetic resonance imaging, and chromosomal studies in next pregnancy. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/ her/their images and other clinical information to be


151



TABLE 2: DESCRIBING VARIOUS OVERLAPPING SYNDROMES WITH FRYNS SYNDROME AND FEATURES TO DIFFERENTIATE FROM FRYNS SYNDROME Syndromes

Gene defect

Features

Distinguishing features from Fryns syndrome

PaIlister‑Killian Syndrome (PKS)

Tetrasomy 12p mosaicism

Sparse hair( characteristic of PKS), syndactyly and streaky skin pigmentation

Donnai‑Barrow syndrome

Autosomal recessive, LRP2

Matthew‑Wood syndrome

autosomal recessive, STRA6

Simpson‑Golabi‑Behmel syndrome

X‑linked disorder, GPC3 or GPC4

Cornelia de Lange syndrome

NIPBL, SMC1A, SMC3, RAD21, and HDAC8

Monosomy 15q26

Interstitial or terminal deletion of distal chromosome15q

Monosomy 8p23.1

Monosomy 8p23.1

It has congenital diaphragmatic hernia (CDH) and/or omphalocele, agenesis of the corpus callosum, intellectual disability, peculiar craniofacial features (ocular hypertelorism, enlarged fontanelle), ocular findings (high myopia, retinal detachment, progressive vision loss, and iris coloboma), and sensorineural deafness, and a characteristic pattern of low molecular weight proteinuria Also known as PDAC (pulmonaryhypoplasia/ agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) Fetures include pre‑ and postnatal macrosomia, distinctive craniofacies (including macrocephaly, coarse facial features, macrostomia, macroglossia, palatal abnormalities) Other features are supernumerary nipples, diastasis recti/umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and GI anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation.Hand anomalies comprise large hands and postaxial polydactyly. Increased risk for development of embryonal tumors (Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma) Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. Growth retardation (