# Handbook of Genetic Counseling/Oral-Facial-Digital Syndrome - Type 1

Oral-Facial-Digital Syndrome - Type 1

## Introduction and Contracting

* What is your understanding about why Dr. wanted to follow up with ____in our genetics clinic?
* What do you already know about OFD syndrome?
* Do you have any questions you would like us to address today?
* What is your main concern?
* Outline the visit
* I have a little family history info from when Dr. visited ____ in the hospital, but I will take a more detailed family history.
* I will also obtain a little more information about _______'s medical history
* Dr. will come in to examine _____ and he will probably want to take a look at some of the features that you (her mother) share with ________.
* We will then discuss the diagnosis of OFD1 including the inheritance, and issues regarding the medical management.

## Diagnosis

* The diagnosis of OFD1 is established by clinical findings
* Established at birth in some infants due to combination of oral, facial, and digital anomalies
* In others it is suspected only after polycystic kidney disease is identified (usually in later childhood or adulthood)
* In some it is only suggested after a woman has an affected child.

## Characteristic Features
### Oral

* tongue is lobed (bifid or trifid)
* tongue nodules (usually hamartomas or lipomas) occur in at least a third of those with OFD1
* ankyloglossia is common (partial or complete fusion of the tongue to the bottom of the mouth) attributable to a short lingual frenulum
* Cleft hard or soft palate, submucous cleft palate, or highly arched palate occur in over half of patients
* Trifurcation of the soft palate has been reported
* Alveolar clefts and accessory gingival frenulae are common (these fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges)
* Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion

### Facial

* Ocular hypertelorism or telecanthus occurs in at least 33%
* Hypoplasia of the alae nasi, median cleft lip or pseudocleft upper lip, and micrognathia are common (exact frequencies unknown )

### Digital

* brachydactyly (short digits), syndactyly (fused digits) of varying degrees, and clinodactyly (inward curvature) of the fifth finger are all common
* other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation
* duplicated hallux (great toe) occurs in less than half of patients and is usually unilateral
* preaxial or postaxial polydactyly of the hands (1-2% of patients)
* Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges

### Brain

* Structural brain abnormalities occur in 10-15% (may be an underestimate)
* most common include
** intracerebral cysts
** agenesis of the corpus callosum
** cerebellar agenesis with or without Dandy-Walker malformation
* Other reported anomalies have each been described in a few patients
** type 2 porencephaly (schizencephalic porencephaly)
** pachygyria (abnormally large convolutions of cerebral cortex) and heterotopias (displacement of gray matter typically into the white matter)
** hydrocephalus
** cerebral or cerebellar atrophy

### Kidney

* polycystic kidney disease (unknown frequency) fewer than 50%
* age of onset most often adulthood (but have been described in children)

### Intellect

* As many as half of the individuals with OFD1 have some degree of mental retardation, which is usually mild
* Depends in part on brain abnormalities, but not always consistent
* Severe mental retardation in the absence of brain malformations appears to be rare

### Other

* Rare manifestations include choanal atresia, tibial pseudarthrosis, and berry aneurysms
* Hair is often described as dry, coarse, and brittle
* Alopecia (absence of hair), usually partial, is an occasional finding
* Milia, small keratinizing cysts, occur in at least 10% (but likely more) occur most often on the scalp, ear pinnae, face, and dorsa of the hands
* milia are usually present in infancy and then resolve, but can then leave pitting scars

## Incidence

* Estimates range from 1/50,000 to 1/250,000

## Inheritance

* OFD1 is inherited in an X-linked dominant manner
* Almost all affected individuals are female
* reports of males with OFD1
** some males are described as malformed fetuses born to women with OFD1
** in most cases the diagnosis is uncertain because the mother is unaffected
* Approximately 75% of cases are sporadic (should examine mother and take family history to determine this)

## Caveats of inheritance

* One family with a peculiar inheritance pattern has been described. In this pedigree, a woman with OFDI had four unaffected sons, three of whom then had daughters all affected with OFDI
* Often, mildly affected female relatives are diagnosed only after the identification of a severely affected individual

## Recurrance risks

* If there is no family history of OFD1, the risk that an unaffected mother of an affected female will have another female with OFD1 is less than 1% due to the possibility of
** 1) a new mutation in a second child
** 2) germline mosaicism in a parent (more likely than new mutation)
*** Germline mosaicism is when a person unaffected by OFD1 has multiple copies of the OFD1 mutation in their gametes
*** Theoretically, germline mosaicism can occur in either parent of a female with OFD1
* At conception, the risk to the offspring of females with OFD1 of inheriting the mutant OFD1 is 50% (most male conceptuses with the mutant OFD1 allele miscarry)
* At delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males
Recurrance is a misspelling. This should instead be 'Recurrence'

## Genetic Testing

* OFD1 is the only gene currently known to be associated with oral-facial-digital syndrome type I
* chromosomal locus Xp22.3-p22.2
* Molecular genetic testing of the OFD1 gene is available on a research basis only
* Tested in a limited number of patients
* A variety of mutations have been identified, the majority result in premature protein truncation
* Detection rate unknown

## Molecular genetics

* Normal allelic variants:
** OFD1 has 23 exons
** OFD1 is on the portion of the X chromosome that escapes inactivation
** OFD1 was expressed in all adult tissues that were examined. However, during early development, expression is exclusively in the genital ridges, soon followed by expression in craniofacial structures and nervous system
** Homologous genes include Cyorf1 (Y chromosomes) and C5orf1 (chromosome 5)
* Pathologic allelic variants:
** Exonic and intronic mutations have both been described
** Mutations in exons include single base pair changes, frameshifts, and deletions
** These changes have occurred to date in exons 3, 11, 13, and 16 only
** Abnormal splicing has also been reported in introns 4 and 5

## Normal gene product

** The protein OFD1 occurs in two forms, Cxorf5-1 and Cxorf5-2, which are differentiated by the use of an alternative splice site
** Cxorf5-1 is a 1011 amino acid protein, whereas Cxorf5-2 is a 367 amino acid protein
** The two proteins share the first 351 amino acids; Cxorf5-2 then has a C-terminal region of 16 amino acids
** The function of the protein is unknown, but thought to be related to a protein-protein interaction mechanism during development

## Abnormal gene product

* Most of the mutations lead to the premature truncation of the protein and are therefore thought to result in a loss of function
* Since this gene is on the portion of the X chromosome that escapes inactivation, the truncated protein may interact with the wildtype product to produce a dominant-negative effect
* No genotype-phenotype correlation exists to date.

## Prenatal testing

* Prenatal testing using molecular genetic techniques is not clinically available
* Prenatal ultrasound examination may detect structural brain malformations and duplicated hallux

## Differential diagnosis

(includes the other oral-facial-digital syndromes and disorders including cystic renal disease)
* OFD II (Mohr syndrome)
** Autosomal recessive
** primarily distinguished by polydactyly (bilateral postaxial polydactyly of hands, bilateral polysyndactly of feet)
** other manifestations include broad (sometimes bifid) nasal tip
** midline partial cleft of lip
** these individuals do not have milia or polycystic kidney disease
* OFD III (Sugarman syndrome)
** Autosomal recessive
** characterized by see-saw winking and polydactyly only postaxial
** myoclonic jerks (also occur)
** bulbous nose (may also occur)
** apparently low set ears (also occur)
* OFD IV (Buru-Baraister syndrome)
** Autosomal recessive
** tibial involvement (short tibia) and pre and or postaxial polydactyly (primary manifestations)
** Other findings include pectus excavatum and short stature
* OFD V (Thurston syndrome)
** Autosomal recessive
** includes polydactyly and median cleft lip only
** Only one affected individual has had hyperplastic frenula
* OFD VI (Varadi-Papp syndrome)
** distinguished by polydactyly (particularly central) and cerebellar malformations
** Renal agenesis and dysplasia have been described
* OFD VII (Whelan syndrome)
** includes unilateral cleft lip and hydronephrosis
** only been described in one mother-daughter pair
** congenital hydronephrosis, coarse hair, facial asymmetry, facial weakness, preauricular tags
** Inheritance either autosomal or X-linked dominant
** may be allelic to OFD1 if X-linked dominant
* OFD VIII
** apparently inherited as an X-linked recessive trait
** combination of polydactyly, tibial and radial defects, and epiglottal abnormalities
** pre and postaxial polydactyly of hans and bilateral duplication of halluces, short stature, bypoplasia of the epiglottis, absent/abnormal central incisors, broad/bifid nasal tip
** may be allelic to OFD1
* OFD IX
** includes retinal abnormalities and nonmedian cleft lip
** reported in three males
* Autosomal dominant polycystic kidney disease (ADPKD)
** In ADPKD cysts develop from tubules, whereas in OFD1 cysts develop from both tubules and glomeruli
** however, imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD and other cystic renal disorders
** cysts are said to be smaller and more uniform in size in OFD1 than in ADPKD, and the kidneys are not as enlarged or deformed in OFD1
** hepatic cysts and berry aneurysms have been observed in OFD1
** Other distinguishing features are mode of inheritance and the lack of oral, facial, digital, or brain abnormalities in ADPKD
* Meckel-Gruber syndrome
** autosomal recessive condition characterized by the combination of encephalocele, polydactyly, and polycystic kidney disease
** Other common findings include microphthalmia (small eyes) or anophthalmia (no eyes), cleft lip/palate, hepatic fibrosis and cysts, and congenital cardiac defects

## Health concerns and management

* Treatment for OFD1 is supportive
* Removal of accessory teeth; orthodontia for malocclusion; and cosmetic or reconstructive surgery for clefts of the lip and/or palate, tongue nodules, accessory frenula, and syndactyly
* Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported
* End stage renal disease (ESRD) has been reported in affected girls and women ranging in age from 11 years to age 70 years
* Management of renal disease may require hemodialysis or peritoneal dialysis and renal transplantation.
* Recently it has been emphasized that the risk for significant renal disease may be greater than previously reported
* Liver and pancreatic cysts may be observed
* Laboratory investigations such as creatinine levels and blood pressure determination to monitor renal function should be done
* if appropriate, imaging studies of the kidneys, liver, and pancreas should be performed

## Patient Resources

(I found no patient literature that I felt was good or appropriate)
* http://www.netnet.net/mums/ -- Website where parents are matched up according to the condition that their child has. There are currently at least 4 people registered with OFD syndrome type I and 15 just listed under OFD syndrome.
* American Cleft Palate-Craniofacial Association
    104 South Estes Drive, Suite 204
    Chapel Hill, NC 27514
    Phone: 919-933-9044
    Fax: 919-933-9604
    Email: cleftline@aol.com
    www.cleftline.org
* National Kidney Foundation
    30 East 33rd Street, Suite 1100
    New York, NY 10016
    Phone: 800-622-9010 or 212-889-2210
    Fax: 212-689-9261
    Email: Info@kidney.org
    www.kidney.org

## References

* Geneclinics-Oral-facial-digital syndrome type 1 (most information came from this reference)
* Smith's Recognizable Pattern's of Inheritance. (p. 262-264) (detailed information about differential diagnosis)

## Notes

The information in this outline was last updated in 2002.