Fryns Syndrome
Encyclopedia
Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period (Alessandri et al., 2005). Fryns (1987) reviewed the syndrome.
,
pulmonary hypoplasia
,
imperforate anus
micropenis
,
bilateral cryptorchidism
,
cerebral ventricular dilation
camptodactyly
,
agenesis
of sacrum
,
low set of ear,
Fryns et al. (1979) reported 2 stillborn
sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy cornea
e, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus
, arhinencephaly, and cardiovascular anomalies (Fitch et al., 1978). 30 PubMed Neighbors
Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge
, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia
, lung hypoplasia, and urogenital abnormalities, including shawl scrotum
, uterus bicornis, and renal cyst
s. They were discordant for diaphragmatic hernia, cleft lip, and Dandy-Walker anomaly
. 30 PubMed Neighbors
Meinecke and Fryns (1985) reported an affected child; consanguinity
of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm
as cardinal features. 30 PubMed Neighbors
Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality
. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism
, small thorax
, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios
with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins. 30 PubMed Neighbors
Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress
. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation
of the cerebral ventricles in both infants. Post-mortem examination showed Dandy-Walker malformation, ventricular septal defect
, and renal cystic dysplasia
. 30 PubMed Neighbors
Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation
therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis
was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax
, he underwent decortication
of the right lung and oversewing of the thoracic duct
. 30 PubMed Neighbors
Kershisnik et al. (1991) suggested that osteochondrodysplasia
is a feature of Fryns syndrome.
Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but was severely retarded
. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older sibs had died in utero
. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients. 30 PubMed Neighbors
Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly
, coarse facial appearance
, hypoplasia of distal phalanges, and an extra pair of rib
s. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients. 30 PubMed Neighbors
Ayme et al. (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch
anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia
, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain
was examined, more than half were found to have Dandy-Walker anomaly and/or agenesis of the corpus callosum
. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia
with rosettes and gliosis
of the retina
, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane. 30 PubMed Neighbors
Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.
In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus
appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy
was noted on serial MRIs
made at 3 months and after 6 months of age.
Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus
, and hypoplastic optic tract
s beyond the optic chiasm
associated with profound mental retardation. 30 PubMed Neighbors
Fryns and Moerman (1998) reported a second-trimester male fetus
with Fryns syndrome and midline scalp
defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures.
Ramsing et al. (2000) described 2 sibship
s with 4 fetuses and 1 preterm baby of 31 weeks' gestation
affected by a multiple congenital disorder
suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma
, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities
with bilateral cleft lip and palate and cardiovascular malformation. 30 PubMed Neighbors
Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis
, central nervous system
defects with left arrhinencephaly and cerebellar hypoplasia
, midline cleft of the upper lip, alveolar ridge
, and maxillary bone, and cleft nose with bilateral choanal atresia
. 30 PubMed Neighbors
Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye
findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia
and cloudy cornea.
Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH. 30 PubMed Neighbors
Ayme et al. (1989) reported prenatal diagnosis
of Fryns syndrome by sonography between 24 and 27 weeks.
Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisor
s; natal teeth had not been mentioned in other cases of Fryns syndrome. 30 PubMed Neighbors
Differential Diagnosis
McPherson et al. (1993) noted the phenotypic
overlap between Fryns syndrome and the Pallister-Killian syndrome
(601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.
Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister-Killian syndrome, noting that differentiation is important to genetic counseling
because Fryns syndrome is an autosomal recessive disorder and Pallister-Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with 'coarse face,' acral hypoplasia, and internal anomalies, the initial diagnosis
of Fryns syndrome had to be changed because mosaicism of isochromosome
12p was detected in fibroblast
cultures or kidney
tissue (Rodriguez et al., 1994). Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister-Killian syndrome by Veldman et al. (2002). 30 PubMed Neighbors
Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta
, dilatation of the ureter
s, proximal thumb
s, and broad clavicle
s. 30 PubMed Neighbors
for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15
, chromosome 6
, and chromosome 22
, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder. 30 PubMed Neighbors
By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 proband
s who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400). 30 PubMed Neighbors
POPULATION GENETICS
In France, Ayme et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live birth
s and perinatal deaths).
Clinical Features
usually associated with diaphragmatic herniaDiaphragmatic hernia
Diaphragmatic hernia is a defect or hole in the diaphragm that allows the abdominal contents to move into the chest cavity. Treatment is usually surgical.The following types of diaphragmatic hernia exist:* Congenital diaphragmatic hernia** Morgagni's hernia...
,
pulmonary hypoplasia
Pulmonary hypoplasia
Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that interfere with normal development of the lungs...
,
imperforate anus
Imperforate anus
An imperforate anus or anal atresia is a birth defect in which the rectum is malformed. Its cause is unknown.-Features:There are several forms of imperforate anus:* A low lesion, in which the colon remains close to the skin...
micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
,
bilateral cryptorchidism
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
,
cerebral ventricular dilation
camptodactyly
Camptodactyly
Camptodactyly is a medical condition involving fixed flexion deformity of the interphalangeal joints of the little finger. This involves permanent flexure of one or more phalanges...
,
agenesis
Agenesis
In medicine, agenesis refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue...
of sacrum
Sacrum
In vertebrate anatomy the sacrum is a large, triangular bone at the base of the spine and at the upper and back part of the pelvic cavity, where it is inserted like a wedge between the two hip bones. Its upper part connects with the last lumbar vertebra, and bottom part with the coccyx...
,
low set of ear,
Fryns et al. (1979) reported 2 stillborn
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
e, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus
Hydrocephalus
Hydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
, arhinencephaly, and cardiovascular anomalies (Fitch et al., 1978). 30 PubMed Neighbors
Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge
Nasal bridge
The nasal bridge is the name given to the upper, bony part of the nose, overlying the nasal bones.A lower or higher than average nasal bridge can be a sign of various genetic disorders, such as fetal alcohol syndrome. A flat nasal bridge can be a sign of Down syndrome, Fragile X syndrome, and Fetal...
, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
, lung hypoplasia, and urogenital abnormalities, including shawl scrotum
Shawl scrotum
Shawl scrotum is a condition in which the scrotum surrounds the penis, resembling a 'shawl'.It is a characteristic of some syndromes such as Aarskog-Scott syndrome , Rubenstein-Taybi syndrome, craniofrontonasal dysplasia, Hunter Carpenter McDonald Syndrome, Naguib Syndrome, Saito Kuba Tsuruta...
, uterus bicornis, and renal cyst
Renal cyst
A renal cyst is a fluid collection in the kidney. There are several types based on the Bosniak classification. The majority are benign, simple cysts that can be monitored and not intervened upon...
s. They were discordant for diaphragmatic hernia, cleft lip, and Dandy-Walker anomaly
Dandy-Walker syndrome
Dandy–Walker syndrome , or Dandy–Walker complex, is a congenital brain malformation involving the cerebellum and the fluid filled spaces around it. A key feature of this syndrome is the partial or even complete absence of the part of the brain located between the two cerebellar hemispheres...
. 30 PubMed Neighbors
Meinecke and Fryns (1985) reported an affected child; consanguinity
Consanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm
Diaphragm
-Optics and photography:* Diaphragm , a stop in the light path of a lens, having an aperture that regulates the amount of light that passes* Diaphragm shutter, a type of leaf shutter consisting of a number of thin blades in a camera-Acoustics:...
as cardinal features. 30 PubMed Neighbors
Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism
Micrognathism
Micrognathism is a condition where the jaw is undersized. It is also sometimes called "Mandibular hypoplasia". It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can hamper...
, small thorax
Thorax
The thorax is a division of an animal's body that lies between the head and the abdomen.-In tetrapods:...
, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios
Polyhydramnios
Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in 0.2 to 1.6% of pregnancies,,...
with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins. 30 PubMed Neighbors
Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress
Infant respiratory distress syndrome
Infant respiratory distress syndrome , also called neonatal respiratory distress syndrome or respiratory distress syndrome of newborn, previously called hyaline membrane disease, is a syndrome in premature infants caused by developmental insufficiency of surfactant production and structural...
. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
of the cerebral ventricles in both infants. Post-mortem examination showed Dandy-Walker malformation, ventricular septal defect
Ventricular septal defect
A ventricular septal defect is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart.The ventricular septum consists of an inferior muscular and superior membranous portion and is extensively innervated with conducting cardiomyocytes.The membranous...
, and renal cystic dysplasia
Dysplasia
Dysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
. 30 PubMed Neighbors
Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation
In intensive care medicine, extracorporeal membrane oxygenation is an extracorporeal technique of providing both cardiac and respiratory support oxygen to patients whose heart and lungs are so severely diseased or damaged that they can no longer serve their function...
therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax
Chylothorax
A chylothorax is a type of pleural effusion. It results from lymphatic fluid accumulating in the pleural cavity.-Causes:...
, he underwent decortication
Decortication
Decortication is a medical procedure involving the surgical removal of the surface layer, membrane, or fibrous cover of an organ. The procedure is usually performed when the lung is covered by a thick, inelastic pleural peel restricting lung expansion. In a non-medical aspect, decortication is...
of the right lung and oversewing of the thoracic duct
Thoracic duct
In human anatomy, the thoracic duct of the lymphatic system is the largest lymphatic vessel in the body. It is also known as the left lymphatic duct, alimentary duct, chyliferous duct, and Van Hoorne's canal....
. 30 PubMed Neighbors
Kershisnik et al. (1991) suggested that osteochondrodysplasia
Osteochondrodysplasia
Osteochondrodysplasia is a general term for a disorder of the development of bone and cartilage .-Achondroplasia:Achondroplasia is a type of autosomal dominant genetic disorder that is a common cause ofdwarfism...
is a feature of Fryns syndrome.
Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but was severely retarded
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older sibs had died in utero
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...
. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients. 30 PubMed Neighbors
Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly
Macrocephaly
Macrocephaly , occurs when the head is abnormally large; this includes the scalp, the cranial bone, and the contents of the cranium.-Causes:...
, coarse facial appearance
Coarse facial features
Coarse facial features refer to a similar change in facial features in the advanced stage of certain conditions like Cretinism, Mucopolysaccharidoses etc, where affected individuals look remarkably similar due to the coarsening of their facial features. These typical coarsening changes include...
, hypoplasia of distal phalanges, and an extra pair of rib
Rib
In vertebrate anatomy, ribs are the long curved bones which form the rib cage. In most vertebrates, ribs surround the chest, enabling the lungs to expand and thus facilitate breathing by expanding the chest cavity. They serve to protect the lungs, heart, and other internal organs of the thorax...
s. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients. 30 PubMed Neighbors
Ayme et al. (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch
Aortic arch
The arch of the aorta or the transverse aortic arch is the part of the aorta that begins at the level of the upper border of the second sternocostal articulation of the right side, and runs at first upward, backward, and to the left in front of the trachea; it is then directed backward on the left...
anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia
Duodenal atresia
Duodenal atresia is the congenital absence or complete closure of a portion of the lumen of the duodenum. -Associated conditions:Approximately 20–40% of all infants with duodenal atresia have Down syndrome....
, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
was examined, more than half were found to have Dandy-Walker anomaly and/or agenesis of the corpus callosum
Agenesis of the corpus callosum
Agenesis of the corpus callosum is a rare birth defect in which there is a complete or partial absence of the corpus callosum. Agenesis of the corpus callosum occurs when the corpus callosum, the band of white matter connecting the two hemispheres in the brain, fails to develop normally,...
. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia
Retinal dysplasia
Retinal dysplasia is an eye disease affecting the retina of animals and, less commonly, humans. It is usually a nonprogressive disease and can be caused by viral infections, drugs, vitamin A deficiency, or genetic defects...
with rosettes and gliosis
Gliosis
Gliosis is a proliferation of astrocytes in damaged areas of the central nervous system . This proliferation usually leads to the formation of a glial scar....
of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane. 30 PubMed Neighbors
Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.
In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
was noted on serial MRIs
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
made at 3 months and after 6 months of age.
Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus
Central sulcus
-External links:* via the Neuroscience Information Framework...
, and hypoplastic optic tract
Optic tract
The optic tract is a part of the visual system in the brain.It is a continuation of the optic nerve and runs from the optic chiasm to the lateral geniculate nucleus....
s beyond the optic chiasm
Optic chiasm
The optic chiasm or optic chiasma is the part of the brain where the optic nerves partially cross...
associated with profound mental retardation. 30 PubMed Neighbors
Fryns and Moerman (1998) reported a second-trimester male fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
with Fryns syndrome and midline scalp
Scalp
The scalp is the anatomical area bordered by the face anteriorly and the neck to the sides and posteriorly.-Layers:It is usually described as having five layers, which can conveniently be remembered as a mnemonic:...
defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures.
Ramsing et al. (2000) described 2 sibship
Sibship
Sibship is a term used in epidemiology and public health to refer to the group or number of children produced by a pair of parents. Thus, siblings constitute a sibship....
s with 4 fetuses and 1 preterm baby of 31 weeks' gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
affected by a multiple congenital disorder
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma
Cystic hygroma
A cystic hygroma is a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck. This is the most common form of lymphangioma. It contains large cyst like cavities containing watery fluid.Microscopically cystic hygroma...
, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities
Craniofacial abnormalities
Craniofacial abnormalities are congenital musculoskeletal disorders which primarily affect the cranium and facial bones.They are associated with the development of the pharyngeal arches.An example is platybasia.-External links:...
with bilateral cleft lip and palate and cardiovascular malformation. 30 PubMed Neighbors
Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis
Gastroschisis
Gastroschisis represents a congenital defect characterized by a defect in the anterior abdominal wall through which the abdominal contents freely protrude. There is no overlying sac and the size of the defect is usually less than 4 cm...
, central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
defects with left arrhinencephaly and cerebellar hypoplasia
Cerebellar hypoplasia
Cerebellar hypoplasia is a developmental disorder characterized by the incomplete or underdevelopment of the cerebellum. It may be genetic or occur sporadically. Cerebellar hypoplasia may be caused by thyroid abnormalities, environmental influences such as drugs and chemicals or viral infections or...
, midline cleft of the upper lip, alveolar ridge
Alveolar ridge
An alveolar ridge is one of the two jaw ridges either on the roof of the mouth between the upper teeth and the hard palate or on the bottom of the mouth behind the lower teeth. The alveolar ridges contain the sockets of the teeth....
, and maxillary bone, and cleft nose with bilateral choanal atresia
Choanal atresia
Choanal atresia is a congenital disorder where the back of the nasal passage is blocked, usually by abnormal bony or soft tissue formed during fetal development.-Presentation:It can be unilateral or bilateral....
. 30 PubMed Neighbors
Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia
Microphthalmia
Microphthalmia also referred to as microphthalmos, nanophthalmia or nanophthalmos, is a developmental disorder of the eye that literally means small eye...
and cloudy cornea.
Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH. 30 PubMed Neighbors
Diagnosis
Prenatal DiagnosisAyme et al. (1989) reported prenatal diagnosis
Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
of Fryns syndrome by sonography between 24 and 27 weeks.
Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisor
Incisor
Incisors are the first kind of tooth in heterodont mammals. They are located in the premaxilla above and mandible below.-Function:...
s; natal teeth had not been mentioned in other cases of Fryns syndrome. 30 PubMed Neighbors
Differential Diagnosis
McPherson et al. (1993) noted the phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
overlap between Fryns syndrome and the Pallister-Killian syndrome
Pallister-Killian syndrome
Pallister–Killian syndrome is an extremely rare genetic disorder occurring in humans. Pallister-Killian occurs due to the presence of the anomalous extra isochromosome 12p, the short arm of the twelfth chromosome. This leads to the development of tetrasomy 12p...
(601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.
Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister-Killian syndrome, noting that differentiation is important to genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
because Fryns syndrome is an autosomal recessive disorder and Pallister-Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with 'coarse face,' acral hypoplasia, and internal anomalies, the initial diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
of Fryns syndrome had to be changed because mosaicism of isochromosome
Isochromosome
An isochromosome is a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm. This is sometimes seen in some females with Turner syndrome or in tumor cells. This may also cause an isochromosome to have two centromeres The chromosome arm is already copied during...
12p was detected in fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
cultures or kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
tissue (Rodriguez et al., 1994). Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister-Killian syndrome by Veldman et al. (2002). 30 PubMed Neighbors
Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
, dilatation of the ureter
Ureter
In human anatomy, the ureters are muscular tubes that propel urine from the kidneys to the urinary bladder. In the adult, the ureters are usually long and ~3-4 mm in diameter....
s, proximal thumb
Thumb
The thumb is the first digit of the hand. When a person is standing in the medical anatomical position , the thumb is the lateral-most digit...
s, and broad clavicle
Clavicle
In human anatomy, the clavicle or collar bone is a long bone of short length that serves as a strut between the scapula and the sternum. It is the only long bone in body that lies horizontally...
s. 30 PubMed Neighbors
Cyrogenetics
In a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2. They suggested that the geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15
Chromosome 15 (human)
right|frame|Human chromosome 15Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 106 million base pairs and represents between 3% and 3.5% of the total DNA in cells.Identifying genes on each chromosome is an...
, chromosome 6
Chromosome 6 (human)
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells...
, and chromosome 22
Chromosome 22 (human)
Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of Chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing between 1.5 and 2 % of the total DNA in cells.In 1999,...
, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder. 30 PubMed Neighbors
By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 proband
Proband
Proband, or propositus, is a term used most often in medical genetics and other medical fields to denote a particular subject being studied or reported on. On pedigrees, the proband is noted with an arrow and the box or circle shaded accordingly...
s who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400). 30 PubMed Neighbors
POPULATION GENETICS
In France, Ayme et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live birth
Live birth
In human reproduction, a live birth occurs when a fetus, whatever its gestational age, exits the maternal body and subsequently shows any sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, for however brief a time and regardless of whether the umbilical cord or...
s and perinatal deaths).