Fryns Syndrome
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Fryns syndrome is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
multiple
congenital anomaly A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth def ...
syndrome that is usually lethal in the
neonatal In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...
period. Fryns (1987) reviewed the syndrome.


Presentation

Usually associated with
diaphragmatic 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. Types * Congenital diaphragmatic hernia ** Morgagni's hernia ** Bochdalek hernia * Hi ...
,
pulmonary hypoplasia Pulmonary hypoplasia is an incomplete development of the lungs, resulting in an abnormally low number or small size of bronchopulmonary segments or alveoli. A congenital malformation, most often occurs secondary to other fetal abnormalities tha ...
,
imperforate anus An imperforate anus or anorectal malformations (ARMs) are birth defects in which the rectum is malformed. ARMs are a spectrum of different congenital anomalies which vary from fairly minor lesions to complex anomalies. The cause of ARMs is unknow ...
,
micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...
, bilateral
cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...
, cerebral ventricular dilation,
camptodactyly Camptodactyly is a medical condition that causes one or more Digit (anatomy), digits (fingers or toes) to be permanently bent. It involves fixed Human anatomical terms#Types of movement, flexion deformity of the proximal interphalangeal articulat ...
,
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. Many forms of agenesis are referred to by individual names, depending on the organ affected: ...
of
sacrum The sacrum (: sacra or sacrums), in human anatomy, is a triangular bone at the base of the spine that forms by the fusing of the sacral vertebrae (S1S5) between ages 18 and 30. The sacrum situates at the upper, back part of the pelvic cavity, ...
, low-set ear.


Cytogenetics

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
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
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 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DNA ...
,
chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...
,
chromosome 8 Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA i ...
and
chromosome 22 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 51 million DNA base pairs and representing b ...
, 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. 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 In medical genetics and other medical fields, a proband, propositus (male proband), or proposita (female proband) is a particular subject (human or other animal) being studied or reported on. On pedigrees, the proband is noted with a square (male) ...
s who had previously been diagnosed with Fryns syndrome and had normal
karyotyping A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...
with G-banded
chromosome analysis Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...
. Two female infants were found to have
microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...
s involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400).


Diagnosis

Prenatal Diagnosis: * Aymé, ''et al.'' (1989) reported
prenatal diagnosis Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problem ...
of Fryns syndrome by
sonography Medical ultrasound includes diagnostic techniques (mainly imaging) using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints ...
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 Incisors (from Latin ''incidere'', "to cut") are the front teeth present in most mammals. They are located in the premaxilla above and on the mandible below. Humans have a total of eight (two on each side, top and bottom). Opossums have 18, wher ...
s; natal teeth had not been mentioned in other cases of Fryns syndrome. Differential Diagnosis: * McPherson et al. (1993) noted the
phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
overlap between Fryns syndrome and the
Pallister–Killian syndrome The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a sma ...
(601803), which is a dysmorphic syndrome with tissue-specific
mosaicism Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is o ...
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 is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...
because Fryns syndrome is an autosomal recessive disorder and Pallister–Killian syndrome is usually a sporadic
chromosomal aberration A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...
. 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 (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
of Fryns syndrome had to be changed because mosaicism of
isochromosome An isochromosome is an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other. The chromosome consists of two copies of either the long (q) arm or the short (p) arm because isochromosome formation ...
12p was detected in
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
cultures or
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
tissue. 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). * 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 The aorta ( ; : aortas or aortae) is the main and largest artery in the human body, originating from the Ventricle (heart), left ventricle of the heart, branching upwards immediately after, and extending down to the abdomen, where it splits at ...
, dilatation of the
ureter The ureters are tubes composed of smooth muscle that transport urine from the kidneys to the urinary bladder. In an adult human, the ureters typically measure 20 to 30 centimeters in length and about 3 to 4 millimeters in diameter. They are lin ...
s, proximal
thumb The thumb is the first digit of the hand, next to the index finger. When a person is standing in the medical anatomical position (where the palm is facing to the front), the thumb is the outermost digit. The Medical Latin English noun for thumb ...
s, and broad
clavicle The clavicle, collarbone, or keybone is a slender, S-shaped long bone approximately long that serves as a strut between the scapula, shoulder blade and the sternum (breastbone). There are two clavicles, one on each side of the body. The clavic ...
s.


Epidemiology

In France, Aymé, ''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 births and
perinatal death Perinatal mortality (PNM) is the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. ''Perinatal'' means "relating to the period starting a few weeks before birth and including the birth and a few weeks after bi ...
s).


Cases

* Fryns et al. (1979) reported 2
stillborn Stillbirth is typically defined as fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. A stillbirth can often result in the feeling of guilt or grief in the mother. T ...
sisters with a multiple congenital anomaly syndrome characterized by coarse
facies In geology, a facies ( , ; same pronunciation and spelling in the plural) is a body of rock with distinctive characteristics. The characteristics can be any observable attribute of rocks (such as their overall appearance, composition, or con ...
with cloudy
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the 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 Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...
, arhinencephaly, and
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
anomalies. * 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 The nasal bridge is the upper part of the nose, where the nasal bones and surrounding soft tissues provide structural support. While commonly discussed in human anatomy, nasal bridges exist in various forms across many vertebrates, particularl ...
, microretrognathia, abnormal helices, and
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
. Other features included distal digital
hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.urogenital The genitourinary system, or urogenital system, are the sex organs of the reproductive system and the organ (biology), organs of the urinary system. These are grouped together because of their proximity to each other, Development of the urinary a ...
abnormalities, including shawl scrotum, uterus bicornis, and
renal cyst A renal cyst is a fluid collection in or on 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. However, some are cancerous or are suspicio ...
s. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly. * Meinecke and Fryns (1985) reported an affected child;
consanguinity Consanguinity (from Latin '':wikt: consanguinitas, consanguinitas'' 'blood relationship') is the characteristic of having a kinship with a relative who is descended from a common ancestor. Many jurisdictions have laws prohibiting people who are ...
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. * 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 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 abnor ...
, small
thorax The thorax (: thoraces or thoraxes) or chest is a part of the anatomy of mammals and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main di ...
, diaphragmatic hernia, distal limb hypoplasia, and early onset of
polyhydramnios Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in about 1% of pregnancies. It is typically diagnosed when the amniotic fluid index (AFI) is greater than 24 cm. There are two clini ...
with
premature delivery Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between ...
. Schwyzer et al. (1987) described an affected infant whose parents were second cousins. * 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 Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that c ...
.
Ultrasonography Medical ultrasound includes diagnostic techniques (mainly imaging) using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints, ...
demonstrated
fetal hydrops Hydrops fetalis or hydrops foetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion is an accumulation of excessive fluid in ...
, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants.
Post-mortem examination An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death; ...
showed Dandy–Walker malformation,
ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. It's a common heart problem present at birth ( congenital heart defect). The extent of the opening may vary ...
, and renal cystic
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...
. * 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 (ECMO) is a form of extracorporeal life support, providing prolonged cardiac and respiratory system, respiratory support to people whose human heart, heart and human lung, lungs are unable to provide an adequa ...
therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus.
Scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a
gastrostomy tube A feeding tube is a medical device used to provide nutrition to people who cannot obtain nutrition by mouth, are unable to swallow safely, or need nutritional supplementation. The state of being fed by a feeding tube is called gavage, enteral fee ...
was inserted. In addition, because of persistent
chylothorax A chylothorax is an abnormal accumulation of chyle, a type of lipid-rich lymph, in the pleural space surrounding the lung. The lymphatic vessels of the digestive system normally return lipids absorbed from the small bowel via the thoracic duct, ...
, he underwent
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 ex ...
of the right lung and oversewing of the
thoracic duct In human anatomy, the thoracic duct (also known as the ''left lymphatic duct'', ''alimentary duct'', ''chyliferous duct'', and ''Van Hoorne's canal'') is the larger of the two lymph ducts of the lymphatic system (the other being the right lymph ...
. * Kershisnik et al. (1991) suggested that
osteochondrodysplasia An osteochondrodysplasia,Etymology: . or skeletal dysplasia, is a disorder of the development of bone and cartilage. Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if t ...
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 had severe
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
. 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 siblings had died
in utero The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic and fetal development of one or more fertilized eggs until bir ...
. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. Nevertheless, intellectual disability has been present in all surviving patients. * Vargas et al. (2000) reported a pair of
monozygotic Twins are two offspring produced by the same pregnancy.MedicineNet > Definition of Twin Last Editorial Review: 19 June 2000 Twins can be either ''monozygotic'' ('identical'), meaning that they develop from one zygote, which splits and forms two e ...
twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had
macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...
, coarse facial appearance, hypoplasia of distal
phalanges The phalanges (: phalanx ) are digit (anatomy), digital bones in the hands and foot, feet of most vertebrates. In primates, the Thumb, thumbs and Hallux, big toes have two phalanges while the other Digit (anatomy), digits have three phalanges. ...
, and an extra pair of
rib In vertebrate anatomy, ribs () are the long curved bones which form the rib cage, part of the axial skeleton. In most tetrapods, ribs surround the thoracic cavity, enabling the lungs to expand and thus facilitate breathing by expanding the ...
s. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild
developmental delay The term developmental delay can refer to: *Global developmental delay, an umbrella term used when children are significantly delayed in two or more areas of development *Specific developmental disorder, a classification of disorders characterize ...
. 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. * Aymé, ''et al.'' (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia,
cleft lip and palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
, cardiac defects, including
septal defect A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at childbirth, birth. A c ...
s and
aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins ...
anomalies, renal cysts,
urinary tract The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...
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 The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
was also often abnormal;
duodenal atresia Duodenal atresia is the congenital absence or complete closure of a portion of the lumen (anatomy), lumen of the duodenum. It causes increased levels of amniotic fluid during pregnancy (polyhydramnios) and intestinal obstruction in newborn babies. ...
, pyloric hyperplasia,
malrotation Intestinal malrotation is a congenital anomaly of rotation of the midgut. It occurs during the first trimester as the fetal gut undergoes a complex series of growth and development. Malrotation can lead to a dangerous complication called volvulus, ...
and common mesentery were present in about half of the patients. When the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
was examined, more than half were found to have Dandy–Walker anomaly and/or
agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres ...
. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed
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. Retinal dysplasia is ...
with rosettes and
gliosis Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes ...
of the
retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
, thickness of the posterior capsule of the lens, and irregularities of Bowman layer. * Alessandri et al. (2005) reported a newborn from the
Comores The Comoros, officially the Union of the Comoros, is an archipelagic country made up of three islands in Southeastern Africa, located at the northern end of the Mozambique Channel in the Indian Ocean. Its capital and largest city is Moroni, ...
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 is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle, a joint, or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus ( myo- "muscle", clonus "spasm") describes a medical sign and, ...
appearing shortly after birth, which was well controlled on
valproate Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...
. Progressive cerebral and brainstem
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
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 In neuroanatomy, the central sulcus (also central fissure, fissure of Rolando, or Rolandic fissure, after Luigi Rolando) is a sulcus, or groove, in the cerebral cortex in the brains of vertebrates. It is sometimes confused with the longitudinal ...
, and hypoplastic
optic tract In neuroanatomy, the optic tract () is a part of the visual system in the brain. It is a continuation of the optic nerve that relays information from the optic chiasm to the ipsilateral lateral geniculate nucleus (LGN), pretectal nuclei, and su ...
s beyond the
optic chiasm In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, ...
associated with profound intellectual disability. * Fryns and Moerman (1998) reported a second-trimester male
fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
with Fryns syndrome and midline
scalp The scalp is the area of the head where head hair grows. It is made up of skin, layers of connective and fibrous tissues, and the membrane of the skull. Anatomically, the scalp is part of the epicranium, a collection of structures covering th ...
defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true
malformation A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
syndrome with major involvement of the midline structures. * Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks'
gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...
affected by a multiple
congenital disorder A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops,
cystic hygroma A cystic hygroma is a form of lymphatic malformation. It is an abnormal growth that usually appears on a baby's neck or head. It consists of one or more cysts and tends to grow larger over time. The disorder usually develops while the fetus is s ...
, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities with bilateral cleft lip and palate and cardiovascular malformation. * Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including
gastroschisis Gastroschisis is a birth defect in which the baby's intestines extend outside of the abdomen through a hole next to the belly button. The size of the hole is variable, and other organs including the stomach and liver may also occur outside the b ...
,
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
defects with left arrhinencephaly and
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellum, cerebellar maldevelopment presenting as early-onset Non-progress ...
, midline cleft of the upper lip,
alveolar ridge The alveolar process () is the portion of bone containing the tooth sockets on the jaw bones (in humans, the maxilla and the mandible). The alveolar process is covered by gums within the mouth, terminating roughly along the line of the mandib ...
, and
maxillary bone In vertebrates, the maxilla (: maxillae ) is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. The two maxillar ...
, and cleft nose with bilateral
choanal atresia Choanal atresia is a congenital disorder where the back of the nasal passage (choana) is blocked, usually by abnormal bony or soft tissue (membranous) due to failed hole development of the nasal fossae during prenatal development. It causes persi ...
. * Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal
eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...
findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral
microphthalmia Microphthalmia (Greek: , ), also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Microphthalm ...
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.


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{{Multiple abnormalities Syndromes affecting the nervous system Syndromes affecting the respiratory system Rare genetic syndromes