The clinical presentation of HFM is quite variable. The severity may depend on the extent of the area with an insufficient blood supply "in utero", and the gestational age of the fetus at which this occurs. In some people, the only physical manifestation may be a small and underdeveloped external ear. In more severe cases, multiple parts of the face may be affected. Some people with HFM may have sensorineural hearing loss and decreased visual acuity or even blindness.

Goldenhar syndrome can be thought of as a particularly severe form of HFM, in which extracranial anomalies are present to some extent. Some of the internal organs (especially the heart, kidneys, and lungs) may be underdeveloped, or in some cases even absent altogether. The affected organs are typically on the same side as the affected facial features, but bilateral involvement occurs in approximately 10% of cases. Deformities of the vertebral column such as scoliosis may also be observed in Goldenhar syndrome.

While there is no universally accepted grading scale, the OMENS scale (standing for Orbital, Mandible, Ear, Nerves and Soft tissue) was developed to help describe the heterogeneous phenotype that makes up this sequence or syndrome.

Intellectual disability is not typically seen in people with HFM.

The Pai Syndrome is a rare subtype of frontonasal dysplasia. It is a triad of developmental defects of the face, comprising midline cleft of the upper lip, nasal and facial skin polyps and central nervous system lipomas. When all the cases are compared, a difference in severity of the midline cleft of the upper lip can be seen. The mild form presents with just a gap between the upper teeth. The severe group presents with a complete cleft of the upper lip and alveolar ridge.

Nervous system lipomas are rare congenital benign tumors of the central nervous system, mostly located in the medial line and especially in the corpus callosum. Generally, patients with these lipomas present with strokes. However, patients with the Pai syndrome don’t. That is why it is suggested that isolated nervous system lipomas have a different embryological origin than the lipomas present in the Pai syndrome. The treatment of CNS lipomas mainly consists of observation and follow up.

Skin lipomas occur relatively often in the normal population. However, facial and nasal lipomas are rare, especially in childhood. However, the Pai syndrome often present with facial and nasal polyps. These skin lipomas are benign, and are therefore more a cosmetic problem than a functional problem.

The skin lipomas can develop on different parts of the face. The most common place is the nose. Other common places are the forehead, the conjunctivae and the frenulum linguae. The amount of skin lipomas is not related to the severity of the midline clefting.

Patients with the Pai syndrome have a normal neuropsychological development.

Until today there is no known cause for the Pai syndrome.

The large variety in phenotypes make the Pai syndrome difficult to diagnose. Thus the incidence of Pai syndrome seems to be underestimated.

Chief markers of Goldenhar syndrome are incomplete development of the ear, nose, soft palate, lip, and mandible on usually one side of the body. Additionally, some patients will have growing issues with internal organs, especially heart, kidneys, and lungs. Typically, the organ will either not be present on one side or will be underdeveloped. Note that while it is more usual for there to be problems on only one side, it has been known for defects to occur bilaterally (approximate incidence 10% of confirmed GS cases).

Other problems can include severe scoliosis (twisting of the vertebrae), limbal dermoids, and hearing loss (see hearing loss with craniofacial syndromes), and deafness or blindness in one or both ears/eyes, Granulosa cell tumors may be associated as well.

The following is a list of symptoms that have been associated with Roberts syndrome:

- Bilateral Symmetric Tetraphocomelia- a birth defect in which the hands and feet are attached to shortened arms and legs

- Prenatal Growth Retardation

- Hypomelia (Hypoplasia)- the incomplete development of a tissue or organ; less drastic than aplasia, which is no development at all

- Oligodactyly- fewer than normal number of fingers or toes

- Thumb Aplasia- the absence of a thumb

- Syndactyly- condition in which two or more fingers (or toes) are joined together; the joining can involve the bones or just the skin between the fingers

- Clinodactyly- curving of the fifth finger (little finger) towards the fourth finger (ring finger) due to the underdevelopment of the middle bone in the fifth finger

- Elbow/Knee Flexion Contractures- an inability to fully straighten the arm or leg

- Cleft Lip- the presence of one or two vertical fissures in the upper lip; can be on one side (unilateral) or on both sides (bilateral)

- Cleft Palate- opening in the roof of the mouth

- Premaxillary Protrusion- upper part of the mouth sticks out farther than the lower part of the mouth

- Micrognathia- small chin

- Microbrachycephaly- smaller than normal head size

- Malar Hypoplasia- underdevelopment of the cheek bones

- Downslanting Palpebral Fissures- the outer corners of the eyes point downwards

- Ocular Hypertelorism- unusually wide-set eyes

- Exophthalmos- a protruding eyeball

- Corneal Clouding- clouding of the front-most part of the eye

- Hypoplastic Nasal Alae- narrowing of the nostrils that can decrease the width of the nasal base

- Beaked Nose- a nose with a prominent bridge that gives it the appearance of being curved

- Ear Malformations

- Intellectual disability

- Encephalocele (only in severe cases)- rare defect of the neural tube characterized by sac-like protrusions of the brain

Mortality is high among those severely affected by Roberts syndrome; however, mildly affected individuals may survive to adulthood

This classification is based on the morphologic characteristics of FND, that describes a variety of phenotypes

Both of these classifications are further described in table 1. This table originates from the article ‘Acromelic frontonasal dysplasia: further delineation of a subtype with brain malformations and polydactyly (Toriello syndrome)', Verloes et al.

In some cases, cleft palate is caused by syndromes which also cause other problems:

- Stickler's Syndrome can cause cleft lip and palate, joint pain, and myopia.

- Loeys-Dietz syndrome can cause cleft palate or bifid uvula, hypertelorism, and aortic aneurysm.

- Hardikar syndrome can cause cleft lip and palate, Hydronephrosis, Intestinal obstruction and other symptoms.

- Cleft lip/palate may be present in many different chromosome disorders including Patau Syndrome (trisomy 13).

- Malpuech facial clefting syndrome

- Hearing loss with craniofacial syndromes

- Popliteal pterygium syndrome

- Treacher Collins Syndrome

This syndrome is characterised by typical facial appearance, slight build, thin and translucent skin, severely adducted thumbs, arachnodactyly, club feet, joint instability, facial clefting and bleeding disorders, as well as heart, kidney or intestinal defects. Severe psychomotor and developmental delay and decreased muscle tone may also be present during infancy. Cognitive development during childhood is normal.

The condition is also known by various other names:

- Lateral facial dysplasia

- First and second branchial arch syndrome

- Oral-mandibular-auricular syndrome

- Otomandibular dysostosis

- Craniofacial microsomia

Malpuech syndrome is congenital, being apparent at birth. It is characterized by a feature known as facial clefting. Observed and noted in the initial description of the syndrome as a cleft lip and palate, facial clefting is identified by clefts in the bones, muscles and tissues of the face, including the lips and palate. The forms of cleft lip and palate typically seen with Malpuech syndrome are midline (down the middle of the lip and palate) or bilateral (affecting both sides of the mouth and palate). Facial clefting generally encompasses a wide range of severity, ranging from minor anomalies such as a (split) uvula, to a cleft lip and palate, to major developmental and structural defects of the facial bones and soft tissues. Clefting of the lip and palate occurs during embryogenesis. Additional facial and ortho-dental anomalies that have been described with the syndrome include: hypertelorism (unusually wide-set eyes, sometimes reported as telecanthus), narrow palpebral fissures (the separation between the upper and lower eyelids) and ptosis (drooping) of the eyelids, frontal bossing (prominent eyebrow ridge) with synophris, highly arched eyebrows, wide nasal root and a flattened nasal tip, malar hypoplasia (underdeveloped upper cheek bone), micrognathia (an undersized lower jaw), and prominent incisors. Auditory anomalies include an enlarged ear ridge, and hearing impairment associated with congenital otitis media (or "glue ear", inflammation of the middle ear) and sensorineural hearing loss.

Another feature identified with Malpuech syndrome is a caudal appendage. A caudal appendage is a congenital outgrowth stemming from the coccyx (tailbone). Present in many non-human animal species as a typical tail, this feature when seen in an infant has been described as a "human tail". This was observed by Guion-Almeida (1995) in three individuals from Brazil. The appendage on X-rays variously appeared as a prominent protrusion of the coccyx. On a physical examination, the appendage resembles a nodule-like stub of an animal tail.

Deficiencies such as mental retardation, learning disability, growth retardation and developmental delay are common. Psychiatric manifestations that have been reported with the syndrome include psychotic behavior, obsessive–compulsive disorder, loss of inhibition, hyperactivity, aggression, fear of physical contact, and compulsive actions like echolalia (repeating the words spoken by another person). Neuromuscular tics have also been noted.

Urogenital abnormalities, or those affecting the urinary and reproductive systems, are common with the syndrome. Malpuech et al. (1983) and Kerstjens-Frederikse et al. (2005) reported variously in affected males a micropenis, hypospadias (a congenital mislocation of the urinary meatus), cryptorchidism ( or undescended testes), bifid (split) and underdeveloped scrotum, and an obstructive urethral valve. An affected boy was also reported by Reardon et al. (2001) with left renal agenesis, an enlarged and downwardly displaced right kidney, cryptorchidism and a shawl scrotum. Other malformations that have been noted with the syndrome are omphalocele and an umbilical hernia.

Congenital abnormalities of the heart have also been observed with Malpuech syndrome. From a healthy Japanese couple, Chinen and Naritomi (1995) described the sixth child who had features consistent with the disorder. This two-month-old male infant was also affected by cardiac anomalies including patent ductus arteriosus (PDA) and ventricular septal defect. The opening in the ductus arteriosus associated with PDA had been surgically repaired in the infant at 38 days of age. A number of minor skeletal aberrations were also reported in the infant, including wormian bones at the lambdoid sutures.

Clinical diagnosis based on orofacial clefts and lip pits typically occurs shortly after birth. Certain defects may be difficult to diagnose, particularly a submucous cleft palate. This form of CP may not be detected except through finger palpation, as the mucosa covering the palate is intact, but the muscles underneath have lost their proper attachments. Feeding problems, impaired speech, and hearing loss are symptoms of a submucous cleft palate. Furthermore, approximately 15% of VWS cases with orofacial clefts, in the absence of prominent lip pits, cannot be easily distinguished from non-syndromic forms of orofacial clefting. Therefore, it is very important to closely examine these patients as well as their relatives for lip pits, especially when there is a family history of mixed clefting, in order to make the VWS diagnosis. Dentists may also play an important role in diagnosing cases not detected at birth, as they detect hypodontia commonly associated with VWS. The

patients most commonly lack the upper second premolars followed by the lower second premolars and upper lateral incisors. The absence of these teeth might play a role in the constricting of the dental arches.

The clinical signs seen in VWS are similar to those of popliteal pterygium syndrome (PPS), which is also an autosomal dominant disease. Approximately 46% of affected individuals have lip pits; other features include genital abnormalities, abnormal skin near nails, syndactyly of fingers and toes, and webbed skin. The disease is also caused by mutations in "IRF6"; however, they occur in the DNA-binding domain of "IRF6" and result in a dominant negative effect in which the mutated IRF6 transcription factor interferes with the ability of the wild type copy to function, in the case of a heterozygous individual.

The classical triad of symptoms that defines 3C syndrome includes certain heart defects, hypoplasia (underdevelopment) of the cerebellum, and cranial dysmorphisms, which can take various forms. The heart defects and cranial dysmorphisms are heterogeneous in individuals who are all classed as having Ritscher-Schinzel syndrome.

Heart defects commonly seen with Ritscher-Schinzel syndrome are associated with the endocardial cushion and are the most important factor in determining a diagnosis. The mitral valve and tricuspid valve of the heart can be malformed, the atrioventricular canal can be complete instead of developing into the interatrial septum and interventricular septum, and conotruncal heart defects, which include tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels, and hypoplastic left heart syndrome. Aortic stenosis and pulmonary stenosis have also been associated with 3C syndrome.

The cranial dysmorphisms associated with 3C syndrome are heterogeneous and include a degree of macrocephaly, a large anterior fontanel, a particularly prominent occiput and forehead, ocular hypertelorism (wide-set eyes), slanted palpebral fissures, cleft palate, a depressed nasal bridge, cleft palate with associated bifid uvula, low-set ears, micrognathia (an abnormally small jaw), brachycephaly (flattened head), and ocular coloboma. Low-set ears are the most common cranial dysmorphism seen in 3C syndrome, and ocular coloboma is the least common of the non-concurrent symptoms (cleft lip co-occurring with cleft palate is the least common).

Cranial dysplasias associated with 3C syndrome are also reflected in the brain. Besides the cerebellar hypoplasia, cysts are commonly found in the posterior cranial fossa, the ventricles and the cisterna magna are dilated/enlarged, and Dandy-Walker malformation is present. These are reflected in the developmental delays typical of the disease. 75% of children with 3C syndrome have Dandy-Walker malformation and hydrocephalus.

Signs and symptoms in other body systems are also associated with 3C syndrome. In the skeletal system, ribs may be absent, and hemivertebrae, syndactyly (fusion of fingers together), and clinodactyly (curvature of the fifth finger) may be present. In the GI and genitourinary systems, anal atresia, hypospadia (misplaced urethra), and hydronephrosis may exist. Adrenal hypoplasia and growth hormone deficiency are associated endocrine consequences of Ritscher-Schinzel syndrome. Some immunodeficiency has also been reported in connection with 3C syndrome.

Many children with the disorder die as infants due to severe congenital heart disease. The proband of Ritscher and Schinzel's original study was still alive at the age of 21.

A fetus with 3C syndrome may have an umbilical cord with one umbilical artery instead of two.

The three most common symptoms of Opitz G/BBB syndrome (both type I & II) are hypertelorism (exceptionally wide-spaced eyes), laryngo-tracheo-esophalgeal defects (including clefts and holes in the palate, larynx, trachea and esophagus) and hypospadias (urinary openings in males not at the tip of the penis) (Meroni, Opitz G/BBB syndrome, 2012). Abnormalities in the larynx, trachea and esophagus can cause significant difficulty breathing and/or swallowing and can result in reoccurring pneumonia and life-threatening situations. Commonly, there may be a gap between the trachea and esophagus, referred to as a laryngeal cleft; which can allow food or fluid to enter the airway and make breathing and eating a difficult task.

Genital abnormalities like a urinary opening under the penis (hypospadias), undescended testes (cryptorchidism), underdeveloped scrotum and a scrotum divided into two lobes (bifid scrotum) can all be commonplace for males with the disease.

Developmental delays of the brain and nervous system are also common in both types I and II of the disease. 50% of people with Opitz G/BBB Syndrome will experience developmental delay and mild intellectual disability. This can impact motor skills, speech and learning capabilities. Some of these instances are likened to autistic spectrum disorders. Close to half of the people with Opitz G/BBB Syndrome also have a cleft lip (hole in the lip opening) and possibly a cleft palate (hole in the roof of the mouth), as well. Less than half of the people diagnosed have heart defects, imperforate anus (obstructed anal opening), and brain defects. Of all the impairments, female carriers of X-linked Type I Opitz G/BBB Syndrome usually only have ocular hypertelorism.

Aneuploidy is often fatal, but in this case there is "X-inactivation" where the effect of the additional gene dosage due to the presence of extra X chromosomes is greatly reduced.

Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and behavioral problems are typical. Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood and have some skeletal anomalies. Skeletal anomalies include:

- Genu valgum

- Pes cavus

- Fifth finger clinodactyly

The effects also include:

- Cleft palate

- Club feet

- Respiratory conditions

- Short or/and broad neck

- Low birth weight

- Hyperextensible joints

- Short stature

- Narrow shoulders

- Coarse features in older age

- Hypertelorism

- Epicanthal folds

- Prognathism

- Gynecomastia (rare)

- Muscular hypotonia

- Hypoplastic genitalia

- Cryptorchidism

- Congenital heart defects

- A very round face in infancy

Most of the signs of MWS are present during the neonatal period. The most common signs at this state are multiple congenital joint contractures, dysmorphic features with mask-like face, blepharophimosis, ptosis, micrognathia, cleft or high arched palate, low-set ears, arachnodactyly, chest deformation as pectus, kyphoscoliosis and absent deep tendon reflexes are frequent minor malformations have also been described and consist of renal anomalies, cardiovascular abnormalities, hypospadias, omphalomesenteric duct, hypertriphic pyloric stenosis, duodenal bands, hyoplastic right lower lobe of the lung, displacement of the larynx to the right and vertebral abnormalities, cerebral malformations.

- 75% of children with MWS have blepharophimosis, small mouth, micrognathia, kyphosis/scoliosis, radio ulnar synostose and multiple contractures.

- They have severe developmental delay; congenital joint contractures and blepharophimosis should be present in every patient

- 2 out of 3 of the following signs should be manifested: post natal growth, mask-like faces, retardation, and decreased muscular mass.

- Some may require additional signs such as; micrognathia, high arched or cleft palate, low set ears, kyphoscoliosis.

- The symptoms of MWS are normally diagnosed during the newborn period

There is much discrepancy in the literature regarding the exact nature of the facial clefting involved in EEC. Some authors claim that the clefting involved in EEC is always cleft lip +/- palate and use this marker as a means of distinguishing EEC from other syndromes, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, and clefting) in which other types of clefting are found. Other authors include cleft palate only (CPO) in conjunction with ectrodactyly and ectodermal dysplasia as sufficient for a diagnosis of EEC.

The main characteristics of 49,XXXXX are intellectual disability, short stature and craniofacial abnormalities. Other physical traits include the following:

- Small head

- Ear abnormalities

- Widely spaced eyes with upward slanting palpebral fissures and epicanthal folds

- Short neck

- Broad nose with a depressed nasal bridge

- Hyperextension of the elbows

- Dental abnormalities and cleft palate

- Clinodactyly of the 5th finger

- Deformities of the feet

- Heart defects

Goldenhar syndrome (also known as oculo-auriculo-vertebral (OAV) syndrome) is a rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip, and mandible. It is associated with anomalous development of the first branchial arch and second branchial arch. Common clinical manifestations include limbal dermoids, preauricular skin tags, and strabismus.

The term is sometimes used interchangeably with hemifacial microsomia, although this definition is usually reserved for cases without internal organ and vertebrae disruption.

It affects between 1/3,500 and 1/26,000 live births, with a male:female ratio of 3:2.

The syndrome is generally diagnosed clinically shortly after birth. The infant usually has respiratory difficulty, especially when supine. The cleft palate is often U-shaped and wider than in cleft palate that is not associated with this syndrome.

Ectodermal dysplasia is characterized by absent sweat glands resulting in dry (hypohydrotic), often scale-like skin, sparse and usually coarse scalp hair that is often blonde, sparse eyebrows and eyelashes, and small brittle nails. In addition, abnormalities of ectodermal derivatives, neuroectodermal derivatives, and mesectodermal derivatives are often found. The ectodermal derivative abnormalities can affect the epidermis including mammary, pituitary and sweat glands, as well as hairs, dental enamel, nails, lens, and the internal ear. Neuroectodermal derivatives that can be affected include sensory placodes, cutaneous pigmental cells, and hair buds. Mesectodermal derivatives affected can include the dermis, hypodermis, dentin, head muscles and conjunctival cells, cervicofacial vascular endothelial cells, and part of the maxillofacial skeleton.

The hypohydrotic symptoms of ectodermal dysplasia described above are evidenced not only in the skin of affected individuals, but also in their phonation and voice production. Because the vocal folds may not be as hydrated as is necessary during the adduction phase of vocal fold vibration (due to lack of lubrication), a complete seal may not be accomplished between the folds and mucosal wave movement may be disrupted. This results in air escapement between the folds and the production of breathy voice, which often accompanies the skin abnormalities of ectodermal dysplasia.

Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital syndrome. It is characterized by facial clefting (any type of cleft in the bones and tissues of the face, including a cleft lip and palate), a appendage (a "human tail"), growth deficiency, intellectual and developmental disability, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Guilliaume Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels and Mingarelli-Carnevale (OSA) syndromes. Mutations in the "COLLEC11" and "MASP1" genes are believed to be a cause of these syndromes. The incidence of Malpuech syndrome is unknown. The pattern of inheritance is autosomal recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.

PRS is characterized by an unusually small mandible (micrognathia), posterior displacement or retraction of the tongue (glossoptosis), and upper airway obstruction. Incomplete closure of the roof of the mouth (cleft palate) is present in the majority of patients, and is commonly U-shaped.

Nasal dysplasia or nasoschisis is caused by a development arrest of the lateral side of the nose, resulting in a cleft in one of the nasal halves. The nasal septum and cavity can be involved, though this is rare. Nasoschisis is also characterized by hypertelorism.

Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate, and cleft palate alone (CP). The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve cleft lip with or without cleft palate. VWS is distinct from other clefting syndromes due to the combination of cleft lip and palate (CLP) and CP within the same family. Other features frequently associated with VWS include hypodontia in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities, syndactyly of the hands, polythelia, ankyloglossia, and adhesions between the upper and lower gum pads.

The association between lower lip pits and cleft lip and/or palate was first described by Anne Van der Woude in 1954. The worldwide disease incidence ranges from 1:100,000 to 1:40,000.

This syndrome is associated with microcephaly, arthrogryposis and cleft palate and various craniofacial, respiratory, neurological and limb abnormalities, including bone and joint defects of the upper limbs, adducted thumbs, camptodactyly and talipes equinovarus or calcaneovalgus. It is characterized by craniosynostosis, and myopathy in association with congenital generalized hypertrichosis.

Patients with the disease are considered intellectually disabled. Most die in childhood. Patients often suffer from respiratory difficulties such as pneumonia, and from seizures due to dysmyelination in the brain's white matter. It has been hypothesized that the Moro reflex (startle reflex in infants) may be a tool in detecting the congenital clapsed thumb early in infancy. The thumb normally extends as a result of this reflex.

Usually associated with diaphragmatic hernia,

pulmonary hypoplasia,

imperforate anus,

micropenis,

bilateral cryptorchidism,

cerebral ventricular dilation,

camptodactyly,

agenesis of sacrum,

low-set ear.

- Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, 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.

- 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 cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.

- 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.

- 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.

- 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.

- 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.

- 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.

- 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 ribs. 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.

- 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, 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.

- 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 tracts beyond the optic chiasm associated with profound mental retardation.

- 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 sibships 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.

- 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.

- 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.