Orofaciodigital syndrome

Orofaciodigital syndrome

Overview

Oro-facial-digital syndrome (OFDS) is a group of rare genetic disorders causing developmental problems in the mouth, face, and fingers/toes, with at least 13 types identified, often including tongue abnormalities (nodules, clefts), cleft lip/palate, dental issues, wide-set eyes, and extra/fused/short digits (polydactyly, syndactyly, brachydactyly). Associated symptoms can also involve brain, kidney, and central nervous system issues, leading to intellectual disability, with different types having varied inheritance patterns (e.g., X-linked for Type 1) and features like polycystic kidney disease. 

Oral-facial-digital syndrome (OFDS) is a group of conditions that affect the development of their oral cavity (mouth, tongue, teeth, and jaw), face (head, eyes and nose) and finger and toes (digits).

Common signs and symptoms include a split (cleft) in the lip and a tongue with an unusual lobed shape. There may also be growth of noncancerous tumors or nodules on the tongue. Affected people may have extra, missing, or differently shaped teeth. Another common feature is an opening in the roof of the mouth (cleft palate). Some people with OFDS have bands of extra tissue (gingival frenula) that attach the lip to the gums. Distinct facial features include a wide nose with a broad, flat nasal bridge and widely spaced eyes (hypertelorism). Fusion of certain digits (syndactyly), short digits (brachydactyly), curved digits (clinodactyly) or extra fingers/toes (polydactyly) are commonly seen in OFDS. People with OFDS also have issues with the development and structure of the brain. Mild to severe intellectual disability is seen in affected people.

There are 14 different types of OFDS, some of which are not well-defined. The signs and symptoms vary widely, making diagnosis difficult. OFDS type I is the most common, but all the OFDS types are very rare. Depending on the type of OFDS there can be other features related with the condition. For example, polycystic kidney disease, seizures, heart defects and distinct skeletal features.

Treatment is mainly supportive and depends on the signs and symptoms seen in each person.

Symptoms

The various types of OFDS present with some combination of signs and symptoms from the list below.

Face and skin: Eyes set widely apart (hypertelorism), small eyes; eyes looking in different directions (strabismus), a small jaw, a loss of hair (alopecia), abnormalities in the structure of the nostrils; broad nose at the base and/or tip; one nostril smaller than the other; angled ears

Oral cavity: split in the lip (cleft lip); opening in the roof of the mouth (cleft palate); lobed or split tongue; tumors of the tongue; extra or missing teeth; smaller than usual jaw; over, under, or lateral bite; bands of extra tissue (gingival frenula) that attach the lip to the gums.

Fingers and Toes features: Extra fingers and/or toes (polydactyly); fused fingers (syndactyly), unusually short fingers (brachydactyly); webbed toes and/or fingers; clubfoot; rigid, bent fingers (clinodactyly)

Intellectual and central nervous system (CNS) problems: Intellectual disability of varying degrees; brain abnormalities; seizures; spastic movement and/or tics; delayed development of speech and motor control

Other: Reduction in growth; heart and kidney problems; sunken chest; vulnerability to respiratory infection

Characteristics associated with specific types of oral-facial-digital syndrome are described below.

OFDS type I disease (Papillon-Leage-Psaume syndrome)

OFDS type I is marked by coarse thin hair, grainy skin lesions (milia) on the face, and extra fingers on one hand (polysyndactyly). Polycystic kidney disease (PKD) is seen in around 50% of patients. PKD may not be seen until the affected person is a teenager.

Oral issues include: clefting of the hard or soft palate, cleft lip, tumors or nodules of the tongue, missing or extra teeth, multiple bands of extra tissue that abnormally attach the lip to the gums (gingival frenulae) and other dental issues. Facial features include widely spaced eyes, broad nasal bridge, small jaw and differently shaped nostrils. Issues with digits affecting the hands more often than the feet. These include short fingers (brachydactyly), fused fingers (syndactyly), bent fingers (clinodactyly) especially the fifth finger and extra fingers or toes (polydactyly).

Adult-onset polycystic kidney disease (PKD) leading to kidney failure is a distinct feature of OFDS type 1. It can be the presenting feature in females with mild signs and symptoms. PKD can lead to end-stage renal disease (ESRD). Central nervous system involvement includes brain malformations. People with OFDS type I have varying degrees of intellectual disability. The condition is mostly lethal in males due to its mode of inheritance. However, a few male patients have been reported. The males had chronic kidney diseases leading to ESRD, but with varying degrees of other oral-facial and digital defects and central nervous system involvement. Signs and symptoms of OFDS type I can vary within and between families.

OFDS type II disease (Mohr syndrome)

Has the same set of symptoms as those of Type I. It may also include the presence of extra toes on both feet (polydactyly) and the nose being split into two parts (bifid nose). Affected people do not have milia or polycystic kidney disease. They have thick hair and rarely have heart problems; cysts or cavities in the brain (porencephaly) or build-up of fluid in the brain (hydrocephaly).

OFDS type III (Sugarman syndrome)

Is characterized by seesaw winking in which the eye blinks (winks) as the jaw moves. Other features seen are extra fingers or toes (polydactyly), epilepsy-like myoclonic jerks, and profound intellectual disability. Some affected people have extra teeth, low-set ears, and broad tip of the nose. End stage kidney failure can occur in the teens and 20s.

OFDS type IV (Baraister-Burn syndrome)

Can be told apart from other types of OFDS by short tibias (bone in the leg, connecting the knee to the ankle) which leads to short limbs. An affected person’s chest may be sunken in. Kidney (renal) cysts, low-set ears and small jaw have been seen in people with OFDS type IV.

OFDS type V (Thurston syndrome)

Is marked by a midline cleft lip and extra fingers and toes (polydactyly) only. Bands of extra tissue that attach the lip to the gums (gingival frenulae) have been reported rarely. This type of OFDS has been seen mostly in people of Indian ancestry.

OFDS type VI (Varadi syndrome)

Is marked by extra toes and fingers. The extra digits are usually located between the second and third digits (central polydactyly). The kidney may be smaller than normal or even absent (renal agenesis/ renal dysplasia). Abnormal brain MRI results showing a molar tooth sign have been noted for people with OFDS type VI. Affected people may have varying degrees of intellectual disability.

OFDS type VII (Whelan syndrome)

Is the same as type I. OFDS type VII has been shown to be due to changes (mutations) in OFD1 gene and is no longer considered a separate type.

OFDS type VIII (Edwards syndrome)

Is characterized by extra fingers and toes (polydactyly) and shortening of some long bones of the arm (radius) and leg (tibia). It is also characterized by issues in the structure of the epiglottis (flap in the throat that prevents food from entering the windpipe and the lungs while swallowing). Other features include a midline cleft lip, large nose and the thumb being split into two (bifid thumb).

OFDS type IX (Gurrieri syndrome)

Clinical features include abnormal development of the retina, and cleft lip (usually lateral/located on the sides of the mouth). Affected people may have one eyeball smaller than the other, short stature, nodules on the tongue, and cleft palate. Heart problems like a hole in the heart (septal defects) have been reported.

OFDS type X (Figuera syndrome)

Common features include cleft palate, flat nasal bridge and gingival frenulae. The lower jaw is set behind the upper jaw (retrognathia) for some affected people. It is marked by the shortening of some long bones of the arm (radius) and the absence of the smaller bone of the lower leg (agenesis of the fibula). Other features seen are the presence of fewer than five fingers or toes on a hand or foot (oligodactyly).

OFDS XI (Gabrielli syndrome/Toriello syndrome)

Is characterized by incomplete or underdevelopment of the odontoid (tooth-like bony structure in the upper spine) and other defects in the spine. Other features seen are enlargement of the ventricles of the brain (ventriculomegaly), small holes near the ears (auricular pits) and underdeveloped eyelids causing them to not open as far as usual (blepharophimosis). Deafness, severe intellectual disability, and behavioural problems have also been seen.

OFDS XII (Moran-Barroso syndrome)

Has been described in only one person who had several malformations of the brain and shortening of the long bone of the leg (tibia). They were also noted to have extra teeth, tongue with a groove, or split (bifid tongue) and a large head (macrocephaly). Along with club feet and extra toes and fingers (polydactyly).

OFDS XIII (Degner syndrome)

Has also been reported in one person. Features include psychiatric issues and epilepsy. Abnormal MRI results showing changes in the appearance of the white matter of the brain (leukokaraiosis) have been seen. The affected person also had tumors of the tongue, cleft lip, and short, bent, and fused fingers (syndactyly).

OFDS type XIV

Includes small size of the head (microcephaly) and intellectual disability. Affected people have abnormal brain MRI results showing a molar tooth sign. Small size of the penis (micropenis) and other common oral features of OFDS have also been seen.

Causes

Chromosomes, which are present in the nucleus of human cells, carry the genetic information (DNA) for each individual. The genetic information is carried in genes. Harmful gene changes (mutations) can cause the gene to not properly. This can lead to genetic conditions.

Specific gene changes have been found for type I, II, III, IV, V, VI, IX and XIV. Genetic causes of the other types of OFDS have not been identified, and some of the genes have only been identified recently. Type X, XI, XII, XIII have been reported in very few people/families and do not have an identified genetic cause. Hence, are thought to occur by chance and are not known to follow a mode of inheritance.

Mode of inheritance of OFDS types:

X-Linked Dominant:

OFDS type I/VII

X-Linked Recessive:

OFDS type VIII

Autosomal Recessive:

OFDS type II, III, IV, V, VI, IX, IV

X-linked Recessive and Dominant Inheritance

X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have only one X chromosome that is inherited from their mother as well as a Y from the father. If a male inherits an X chromosome that contains a non-working gene, he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome (not the X) to male children.

X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have just one X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive.

The following types of OFSD have shown to follow an X-linked inheritance pattern:

OFDS type I is associated with changes (mutations) in the OFD1 gene (previously called CXORF5). The gene is located on the X chromosome and follows an X-linked dominant pattern of inheritance. Approximately 75% of females with OFDS type 1 have no family history of OFDS.

OFDS Type VIII is inherited in an X-linked recessive form, but a gene has not been associated with this type.

Autosomal Recessive Inheritance

Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a high chance to carry the same change (mutation). Hence, increasing the risk to have children with recessive genetic conditions, compared to unrelated parents.

The following types are known to follow autosomal recessive inheritance:

OFDS Type II has been linked with mutations in the NEK1 gene.

OFDS type III has been linked with mutations in the TMEM231 gene.

OFDS type IV has been linked with mutations in the TCTN3 and WDPCP genes.

OFDS type V has been linked with mutations in the DDX59 gene.

OFDS type VI has been linked with mutations in the OFD1, TMEM216, C4orf42, TMEME138, TMEM107 and KIAAO753 genes. Different changes (mutations) in these genes are also known to cause other conditions like Joubert Syndrome and Meckel-gruber Syndrome.

OFDS type IX has been linked with mutations in the SCLT1 and TBC1D32/C6orf170 genes.

OFDS type XIV has been linked with mutations in the C2CD3 gene.

Affected populations

All types of oral-facial-digital syndrome are rare, with type I being the least rare. The incidence of OFDS type I is thought to be between 1 per 50,000 births and 1 per 250,000 births, and type II is thought to occur 1 in 300,000 births. Some types of OFDS have only been reported in a few people/families.

Disorders with Similar Symptoms

Symptoms of the following conditions can be similar to those of OFSD syndrome. Comparisons may be useful to help make a diagnosis:

Juberg-Hayward syndrome (orocraniodigital syndrome) is a rare disorder characterized by cleft lip and palate, a smaller than the normal sized head, abnormal number and development of the thumbs and toes, and growth hormone deficiency resulting in short stature.

Nager acrofacial dysostosis/AFD/ Nager type/Mandibulofacial dysostosis is a rare disorder that affects the limbs and face. This results in cleft lip and palate, abnormal development of bones of the jaw and arms, and smaller than normal thumbs. The condition is caused by mutations in the SF3B4 gene. While most cases occur in families with no prior history of the disorder, autosomal dominant and autosomal recessive inheritance have been reported.

Some people who were given the diagnosis of Autosomal dominant polycystic kidney disease (ADPKD) diagnosis who were later found to have mutations in the OFD1 gene. The origin and size of the cysts in the kidneys differs between OFDS type I and ADPKD. Other differentiating features are the mode of inheritance and the absence of oral, facial, digital, or brain defects in ADPKD. The two genes in which changes (mutations) are known to cause ADPKD are PKD1 and PKD2.

Multiple genes associated with OFDS are also known to cause ciliopathies (a category of diseases thought to be caused by dysfunction of cilia and flagella) like Joubert Syndrome and Meckel-Gruber Syndrome. Changes (mutations) in TMEM216, TMEM138, TMEM231, TMEM107, OFD1 and C5orf42/CPLANE1 are known to cause OFDS type VI and Joubert Syndrome. Changes (mutations) in TMEM231, TCTN3, TMEM107 and C5orf42/CPLANE1 are also known to cause Meckel-Gruber Syndrome.

Joubert syndrome is a hereditary neurological disorder marked by malformation of the area of the brain which controls balance and coordination. Issues with muscles and eye movement similar to those of oral-facial-digital syndrome occur. The molar tooth sign is seen on brain MRI. Weak muscle tone (hypotonia), abnormal breathing patterns and eye movement are seen, along with intellectual disability. There are multiple genes known to cause Joubert Syndrome, many of which overlap with OFDS. Inheritance is usually autosomal recessive, but rarely it may be X-linked recessive

Meckel-Gruber syndrome is characterized by nervous system malformations, multiple cysts in the kidneys, extra digits (polydactyly), and leads to an early death. Other findings include cleft lip and palate, problems with development of external genital organs, small head (microcephaly), and one or both eyeballs being small (microphthalmia). Affected people also have multiple other defects of the eye, especially the retina. It is also inherited in an autosomal recessive manner.

Diagnosis

Diagnosis of OFD syndromes with a known genetic cause (OFDS type I, III, IV, V, VI, IX, XIV) can be confirmed by genetic testing. However, diagnosis is generally made based on the clinical symptoms presented. 

Clinical Testing and Work Up 

The initial workup for people with OFDS includes:  

Exam of the face, especially the mouth, and the hands for typical signs and symptoms.  

Formal, age-appropriate testing of development and behavior. 

Imaging of the brain. 

Checking the blood pressure and serum creatinine concentration (especially for people with OFDS type I).  

Analysis of the urine, other blood tests (serum chemistries), and ultrasound examination of the kidneys, liver, ovary, and pancreas for cysts if the person is age ten years or older (especially for people with OFDS type I).  

Formal hearing examination if cleft palate is present.  

Consultation with a clinical geneticist and/or genetic counselor.  

Surveillance for people with OFDS type I includes the following: 

Annual audiology (ear) evaluation and testing of speech development and frequency of ear infections in children if cleft lip and/or cleft palate is present. 

Annual blood pressure examination and serum creatinine concentration to monitor kidney function in those ten years or older.  

Annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease in people ten years or older.  

Surveillance for OFDS types having brain malformations features can include receiving regular brain MRIs.  

Standard Therapies

Treatment

Treatment of oral-facial-digital syndrome may involve reconstructive surgery for facial clefts, removal of extra teeth, surgery to repair fused fingers or digit anomalies. It can also include management of renal disease including hemodialysis/peritoneal dialysis or a kidney transplant. Management of seizures if present and evaluations for learning disabilities may be required based on the type. Speech therapy and special education may be recommended as well. Other treatment is supportive and based on symptoms. Genetic counseling is recommended for patients and their families

Type of Doctor Department : Geneticist/Clinical Geneticist , Oral & Maxillofacial Surgeon / Plastic Surgeon, Orthopedic Surgeon , Neurologist , Ophthalmologist, Developmental Therapists (PT/OT/Speech),Nephrologist