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Four novel mutations in the OFD1 (Cxorf5) gene in Finnish patients with oral-facial-digital syndrome 1 [5]

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Four novel mutations in the
OFD1 (Cxorf5)
gene in
Finnish patients with oral-facial-digital syndrome 1
A Rakkolainen, S Ala-Mello, P Kristo, A Orpana, I Järvelä
J Med Genet
Oral-facial-digital syndrome type 1 (OFD1, MIM
311200) was first described by Papillon-Léage and
Psaume1in 1954 and further delineated in 1962 by
Gorlin and Psaume,2who called it orodigitofacial dysostosis. It
is a multiple congenital anomaly syndrome characterised by
malformations of the face, oral cavity, and hands and feet. The
facial dysmorphic features include hypertelorism, frontal
bossing, broad nasal bridge, hypoplasia of alar cartilage, and
transient milia. Oral cavity malformations include often
asymmetrical cleft of the palate (80%), small midline cleft of
the upper lip (45%), clefts of the tongue, hamartomatous
masses on the ventral surface of the tongue (70%), mucobuc-
cal fibrous bands, and dental abnormalities. Malformations of
the fingers are seen in 50-70% and toe malformations in 25%.
Central nervous system abnormalities, such as hydrocephalus,
porencephaly, and agenesis of the corpus callosum, with mild
mental retardation are seen in 40%.3In recent years, a kidney
disease closely resembling adult type polycystic kidney disease
has been shown to be one of the distinct features of this
At least nine different forms of oral-facial-digital syn-
dromes have been described, type 1 being the most common
with a suggested incidence of 1:50 000 live births. OFD1 syn-
drome has dominant X linked inheritance with lethality in
males. However, a case of Klinefelter syndrome (XXY) with
OFD1 has been reported.6
By linkage analysis in two kindreds, the locus for OFD1 was
mapped to Xp22.3-22.2.7Recently, the gene for OFD1, Cxorf5,
was identified, and mutations of three familial and four
sporadic cases were identified by Ferrante et al.8Expression of
the gene was seen in all the tissues affected in the syndrome.
We report here the identification of four novel mutations in
the OFD1 gene together with the clinical findings in four
Finnish families, of which two are familial and two sporadic.
The patients were ascertained from the Cleft Centre of the
Department of Plastic Surgery, Helsinki University Central
Hospital, where all patients with cleft lip and/or palate nation-
wide are treated. In addition, patients were ascertained from
the Department of Medical Genetics of The Family Federation
of Finland, which serves the whole country, and the Clinical
Genetics Unit of Helsinki University Central Hospital, which
serves the densely populated south of Finland in clinical
genetics. All the patients were examined (fig 1) and their files
and hospital records analysed by one of the authors (SA-M).
Mutation analysis
DNA extracted from peripheral EDTA blood of the patients
was screened for mutations in the OFD1 gene using primer
sequences kindly provided by Dr Brunella Franco from
Telethon Institute of Genetics and Medicine (TIGEM). PCR
amplifications of the samples were run through 35 cycles con-
sisting of 40 seconds at 94°C (denaturation), 40 seconds at 55
or 50°C (annealing), and one minute at 72°C (extension) with
Figure 1 The family pedigrees of the Finnish OFD1 families. Black symbols, affected; symbols with slashed lines, anamnestically affected.
the final extension step of 5-10 minutes covering all 23 exons.
Sequencing of PCR products was performed using ABI
PRISM7 BigDye Terminator Cycle Sequencing Kit, Version 2.0
(Applied Biosystems, Foster City, CA, USA) in both directions
and analysed using an ABI PRISM7 3100 Genetic Analyzer
according to the manufacturer’s instructions. The presence of
a mutation was confirmed by minisequencing9of the DNA in
each family member. To exclude the presence of each of the
mutations in random subjects, DNA extracted from buffy coat
samples of 50 anonymous Finnish blood donors were analysed
by minisequencing.
Ethical approval for the study was obtained from the ethical
committee of Helsinki University Hospital and the Finnish
Red Cross Transfusion Service.
RNA analysis
RNA was isolated from heparin blood samples of the control
and the youngest patient from family I (fig 1) carrying the
intronic mutation IVS5-10T>G using the QIAamp RNA
Blood Mini kit (Qiagen, Hilden, Germany). This mutation
generates a putative novel splice site in exon 6. The mRNA
was reverse transcribed to cDNA using 1 µg of total RNA, 10
units of AMV reverse transcriptase (Promega M5101) in the
presence of 20 units of recombinant RNase inhibitor (RNasin,
Promega, N2511), and 25 nmol dNTPs. The reaction was
allowed to take place at 42°C for one hour, after which the
cDNA was diluted with 1.7 volumes of DNA-TE-Buffer (10
mmol/l Tris-HCl, pH 7.8, 1 mmol/l EDTA) and stored at 20°C.
cDNA synthesis was primed with the antisense primer
coding sequence of exon 6 of the OFD1 mRNA. For PCR two
sense primers were designed. The first one, 5-
together with the reverse primer used in the reverse
transcription flanked the putative new splice site. The second
TTTAGGTTT-3was designed to anneal exclusively over the
putative novel splice site to give a product only if this putative
new splice site was transcribed (fig 2).
We found four novel mutations in the OFD1 gene (table 1, fig
3) in two sporadic patients and in two families, both contain-
ing three patients with OFD1 syndrome (fig 1). The clinical
features of the patients shown in table 2 were characteristic of
OFD1 syndrome. In each case a novel mutation in the recently
discovered OFD1 gene was identified; two of them were
frameshifts, one was a missense mutation, and one was a
splice mutation.
In family I, the syndrome was diagnosed in three successive
generations (fig 1). The grandmother’s facial features were
typical of OFD1. She did not have cleft palate like her daugh-
ter and granddaughter. Instead, alveolar notching with miss-
ing teeth were seen. No abnormalities of the hands were seen.
At the age of 44 years, she had just undergone a kidney trans-
plant because of polycystic kidney disease. The kidney disease
had been discovered by chance on routine gynaecological
examination one year earlier and dialysis treatment was
started almost immediately after that. She was unwilling to
participate in genetic DNA studies. The daughter had small
hands and feet with brachydactyly of the fifth fingers. The
syndactyly of her fourth and fifth fingers of the left hand had
been operated on as a child. Renal ultrasonography was
performed at the age of 23, when the diagnosis of OFD1 was
confirmed. Multiple cysts were seen in the right kidney,but no
signs of renal failure in the laboratory examinations was
found. The granddaughter, aged 1.5 years, has developed nor-
mally. In the extremities, there was only mild clinodactyly of
the fifth fingers. The cleft palate was asymmetrical. Alveolar
notching, suggesting tooth aplasia, and mucobuccal fibrous
bands were seen. No signs of retardation were detected in this
family. We found a T>G change in intron 5 of the OFD1 gene
in the daughter and the granddaughter. The mutation is
located 10 nucleotides before the starting nucleotide of exon 6
(fig 3) where it creates a novel splice acceptor site (and adds
three novel amino acids to the 5end of exon 6) resulting in an
alternative splicing of mRNA. This was confirmed by the RNA
studies described in the Methods section (fig 4).
In family II (fig 1), the mother and her two daughters were
clinically examined and their facial features and other signs
were typical of OFD1 syndrome (table 2). All three patients
studied had midline pseudocleft of the upper lip, but no
operations had been performed. The tongues of the mother
and the older daughter were bilobulated and the younger
daughter had multiple lobules in her tongue. No-one in this
family had had problems with kidney function and no ultra-
sonographic examinations of the kidneys were performed. At
the age of 42 years, the mother was diagnosed with
hyperthyreosis, which was treated with radioactive iodine.
The younger daughter had been operated on at the age of 1
year because of a medially located, supernumerary distal
phalanx in the right hallux. The left leg grew 3 cm longer
than the right leg and at the age of 13 years an orthopaedic
operation was performed. The left breast has grown bigger
than the right with mastopathic changes. Her mental devel-
opment has been mildly delayed and she attended a special
school. In the older daughter, vaginal bleeding started at the
age of 3 months. After investigations, hormonal medication
was given for precocious puberty. Epileptic seizures began at
the age of 2
years. Repeated CT scan of the brain showed a
hypothalamic hamartoma, which was thought to be the rea-
son for the precocious puberty through excretion of hypotha-
lamic hormones. She had short stature with a final height of
1.45 m (3.5 SD) and small hands and feet. The fourth meta-
tarsals were short, especially in the right foot. She attended a
Figure 2 Diagram of detection of the transcript showing the
abnormal splicing caused by the IV5-10T>G mutation in exon 6 of
Exon 5
Exon 5 Exon 6Mut
Exon 5 Exon 6
RT-PCR product (+)
RT-PCR product (–)WT
Exon 6
IVS5-10T>G Table 1 Mutations in patients with OFD1
(case*) Location Nucleotide change† Effect on protein
I (F) Intron 5 IVS5-10T>G Abnormal splicing
II (F) Exon 16 1887-1888insAT Frameshift
III (S) Exon 3 235G>A A79T†
IV (S) Exon 13 1409delA Frameshift
*F=familiar, S=sporadic.
†Mutation description is according to Antonarakis
et al
12 with the
cDNA sequence of
used as the reference and with the ATG
translation initiation codon denoted as nucleotide +1.
Letters 293
special school for handicapped children because of moderate
mental retardation and received medication for psychiatric
symptoms for a couple of years. In this family, an insertion of
AT between nucleotides 1887 and 1888 in exon 16 was
detected in all three family members (fig 3). This creates a
frameshift resulting in a premature stop codon (TAG) at
amino acid position 666 of the OFD1 gene.
In family III, the only patient studied had syndactyly of the
fourth and fifth fingers of the left hand that had been oper-
ated on at the ages of 5 and 11 years. On ultrasonographic
Table 2 Clinical features of the patients with OFD1
I.3 I.2 IV III II.3 II.2 II.1
Age (years) 1.5 23 0.5 30 19 25 50
Clinical findings
Midfacial flattening ++++−−+
Alar hypoplasia +++++++
Dystopia canthorum + + + ++
Skin milia + +−−−−
Thinupperlip +++++++
Cleft palate + + −−−−−
Midline pseudocleft of upper lip −−−−+++
Alveolar notching ++++++
Toothaplasia NA+NA++++
Lobulated tongue +++++++
Tongue hamartoma + + + ++
Multiple frenula +++++
Mental retardation −−−−++
Polycystic kidneys ND + ND + ND ND ND
Extremities +++++++
NA=not yet available, ND=not done.
Figure 3 Sequencing chromatograms showing the four
mutations in the Finnish patients.
294 Letters
examination, numerous small cysts were detected in both
kidneys at the age of 29 years. Functional studies of the
kidneys were normal. In this patient a missense mutation
G>A at nucleotide 235 in exon 3 was identified (table 1, fig
3). This transversion leads to a change of a non-polar amino
acid alanine (A) to an uncharged polar amino acid threonine
(T). We analysed DNA samples from both parents by minise-
quencing and no abnormalities were found, indicating that
this is a de novo mutation.
In family IV, the index case was first examined at the age of
6 months. The first diagnostic signs were a prominent metopic
ridge and a soft nodule (about 0.5 cm in diameter) medially in
the right hallux. Psychomotor development has proceeded
within normal limits. In this patient, a deletion of A at nucleo-
tide 1409 in exon 13 leading to a frameshift was identified.
This mutation results in a premature stop codon (TAG) at
position 472. DNA from both parents was analysed and no
mutations were found.
None of the four mutations was identified in the DNA of 50
anonymous Finnish blood donors screened by minisequenc-
The results of the RT-PCR experiments (fig 4) show that in
both the patient and the control sample the products
generated by RT-PCR amplifying the area flanking the putative
novel splice site are of similar size, indicating that the normal
sized mRNA could be found in both samples. However, the
splice site specific RT-PCR resulted in the identification of the
product only in the patient’s sample. This indicates that the
intronic nucleotide change T >G residing 10 nucleotides from
the splice acceptor site of exon 6 generates a false splice site
and so is most likely the cause of the disease in this patient.
Eight OFD1 patients have been diagnosed in Finland, consist-
ing of a population of about 5 million, during the last 20 years.
In all of them, a mutation in the recently identified OFD1
(Cxorf5) gene was found. Two of them were nonsense, one
missense, and one splice mutation. The clinical features were
characteristic in every patient. Interestingly, one of our
patients had short fourth metatarsals, similar to a patient
described by Ferrante et al.8Mild or moderate mental retarda-
tion was seen in one of the families with the two daughters
with learning difficulties.
Renal involvement in OFD1 cases may be as high as 50%.10
In three out of eight Finnish patients, polycystic kidney
disease was present, and one of them received a new kidney at
the age of 44 years. The mutations that were associated with
polycystic kidney disease in the Finnish patients were the
splice mutation in intron 5 and a missense mutation G>A at
nucleotide 235 in exon 3. In the original report by Ferrante et
al,8polycystic kidney disease was also associated with
mutations in exon 3 but also in intron 4. Polycystic kidney
disease usually manifests in adulthood, so two of our patients
are too young to be able to draw any conclusions about kidney
When analysing the phenotype-genotype correlation con-
cerning mental retardation associated with this syndrome,
mild to moderate mental retardation or learning difficulties
were reported with mutations in exons 3, 13, and 16, and
intron 4 in the original study.8In this study, only the
frameshift mutation in exon 16 was associated with learning
difficulties in two out of three members of the same family.
Further studies are needed to know whether certain
mutations are more frequently associated with kidney disease
or mental retardation, the findings that are important in
genetic counselling when predicting the outcome of the
The OFD1 gene contains 23 coding exons (GenBank acces-
sion numbers Y15164 and Y16355) with unknown function.11
Interestingly, three of the mutations found in this study are
located in the same exons 3, 13, and 16 as the mutations
reported in the original study by Ferrante et al,8suggesting
that these exons might represent regions for mutational hot
spots. Functional studies of both the wild type OFD1 gene and
the mutants are needed to understand the disease mechanism
underlying OFD1.
In conclusion, we report here the identification of four novel
mutations in the OFD1 gene in seven Finnish patients with
oral-facial-digital syndrome type I. Our results confirm the
causative role of the OFD1 gene in the pathogenesis of this
We are grateful to the patients and their families for their
participation in this study. We thank Sirkka Elfving and Eino
Puhakainen for encouragement during this study and the personnel
Figure 4 The RT-PCR-products covering exons 4-6 are normal in
both control and patient samples (on the left). The intronic nucleotide
change IVS5-10T>G results in an abnormally spliced product in the
patient sample (RT(+)) compared to the normal sample (RT(+)). RT()
samples are the control samples with no cDNA.
Φ X174
Control, RT(+)
Control, RT(–)
Patient, RT(+)
Patient, RT(–)
Ex4 – Ex6
Φ X174
Control, RT(–)
Patient, RT(+)
Patient, RT(–)
Control, RT(+)
Splice site mutation
+Oral-facial-digital syndrome type 1 (OFD1) is an X linked
dominant disorder characterised by malformations in the
face, oral cavity, and digits with a wide phenotypic vari-
ation. Recently, mutations in the
gene (
Xp22 were found to underlie OFD1. We report here the
identification of four novel mutations in the
in the Finnish families, two of which are familial and two
+In the familial cases a splice mutation T>G in intron 5 in
the mother and her daughter was identified resulting in
an abnormal splicing, and in the second family a
nonsense mutation 1887-1888insAT in exon 16 was
detected in the mother and her two daughters. Analysis
of the sporadic cases showed a missense mutation
235G>A in exon 3 and a single nucleotide deletion
1409delA leading to a nonsense mutation in exon 13.
Three of the mutations in this study were located in the
same exons as in the original study.
+Our study confirms the causative role of the
in the pathogenesis of oral-facial-digital syndrome type
Letters 295
of the Laboratory of Molecular Genetics for technical help. Financial
support from Helsinki University Hospital Research Funding is
Authors’ affiliations
A Rakkolainen, A Orpana, Department of Clinical Chemistry,
University of Helsinki, Helsinki, Finland
A Rakkolainen, S Ala-Mello, P Kristo, A Orpana, I Järvelä,
Department of Medical Genetics, University of Helsinki and
HUCH-Laboratory Diagnostics, Helsinki, Finland
S Ala-Mello, Clinical Genetics Unit, HUCH-Laboratory Diagnostics,
Helsinki, Finland
Correspondence to: Dr I Järvelä, HUCH-Laboratory Diagnostics,
Laboratory of Molecular Genetics, Haartmanink 2, 00290 Helsinki,
1Papillon-Léage, Psaume J. Une malformation hereditaire de la
maqueuse buccale: brides et freins anormaux.
Rev Stomatol
2Gorlin RJ, Psaume J. Orodigitofacial dysostosis - a new syndrome.
3Odent S, Le Marec B, Toutain A, David A, Vigneron J, Tréguier C, Jouan
H, Milon J, Fryns JP, Verloes A. Central nervous system malformations
and early and end-stage renal disease in oro-facio-digital syndrome type
Am J Med Genet
4Connacher AA, Forsyth CC, Stewart WK. Orofaciodigital syndrome
type I associated with polycystic kidneys and agenesis of the corpus
J Med Genet
5Donnai D, Kerzin-Storrar L, Harris R. Familial orofaciodigital syndrome
type I presenting as adult polycystic kidney disease.
J Med Genet
6Wahrman J, Berant M, Jacobs J, Aviad I, Ben-Hur N. The
oral-facial-digital syndrome: a male lethal condition in a boy with 47 XXY
7Feather SA, Woolf AS, Donnai D, Malcolm S, Winter RM. The
oral-facial-digital syndrome type I (OFD1), a cause of polycystic kidney
disease and associated malformations, maps to Xp22.2-Xp22.3.
Mol Genet
8Ferrante MI, Giorgio G, Feather SA, Bulfone A, Wright V, Ghiani M,
Selicorni A, Gammaro L, Scolari F, Woolf AS, Odent S, Le Marec B,
Malcolm S, Winter R, Ballabio A, Franco B. Identification of the gene for
oral-facial-digital type I syndrome.
Am J Hum Genet
9Syvanen AC, Ikonen E, Manninen T, Bengtstrom M, Soderlund H, Aula
P, Peltonen L. Convenient and quantitative determination of the frequency
of mutant alleles using solid-phase minisequencing: application to
aspartylglucosaminuria in Finland.
10 Salinas CF, Pai GS, Vera CL, Milutinovc J, Hagerty R, Cooper JD,
Cagna DR. Variability of expression of the orofaciodigital syndrome type
I in black females: six cases.
Am J Med Genet
11 de Conciliis L, Marchitiello A, Wapenaar MC, Borsani G, Giglio S,
Mariam M, Consalez GG, Zuffardi O, Franco B, Ballabio A, Banfi S.
Characterization of Cxorf5 (71-7A), a novel human cDNA mapping to
Xp22 and encoding a protein containing coiled-coil α-helical domains.
12 Antonarakis SE, the Nomenclature Working Group. Recommendations
for a nomenclature system for human gene mutations.
Hum Mutat
Genes predict outcome in multiple
Pairs of siblings with multiple sclerosis show the same progression of their disease and the same
eventual disability and handicap, supporting the theory that genes rather than environment dictate
both susceptibility to multiple sclerosis and its outcome.
This is the conclusion of Chataway et al, who have added to the first UK cohort of 177 sibling pairs with
multiple sclerosis from 166 families and reanalysed the data for the new total of 262 pairs from 250
families. As before, they looked for concordance in clinical variables in each pair of siblings for course of
disease, presenting symptoms, age and year of onset—and this time also included measures of disability,
disease progression, and handicap. The data were adjusted for confounding factors associated with
analysis of sibling pairs and were analysed with statistical techniques that can include potentially con-
founding variables.
A third of all sibling pairs had similar presenting symptoms, but this was not statistically significant,
nor was the primary affected site. However, 50% of the sibling pairs had an identical course of their mul-
tiple sclerosis—relapse-remitting, primary progressive, or secondary progressive—which was a
significant result. Severity of the disease at assessment indicated that disability, progression, and handi-
cap were concordant within sibling pairs but relapse rate in the previous year was not.
So although most members of sibling pairs have different initial symptoms, the progress of their dis-
ease will converge such that each sibling in a pair will eventually have similar disability and handicap
Journal of Neurology Neurosurgery and Psychiatry
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296 Letters
... It has been suggested that OFD1 mutations that truncate the protein before Asn630 are embryonic lethal in males and cause OFD type I in females. 16,39 All the identified mutations caused truncations prior to Asn630 (Fig 2B, dashed line). Because somatic OFD1 truncation mutations were exclusively identified in male individuals, OFD1 function must be severely impaired in all cells possessing the mutation, suggesting that an absence of OFD1 activity is required for hamartoma formation. ...
... (B) Three coiled coil domains and a LIS1 homology domain (LisH) of OFD1 are shown (UniProt KB, O75665). Truncation mutations in OFD1 prior to Asn630 have been reported to cause OFD type I in females and embryonic lethality in males 16,39 . All the identified mutations caused truncations prior to Asn630 (dashed line). ...
Full-text available
Objective: Hypothalamic hamartoma (HH) is a congenital anomalous brain tumor. Although most HHs are found without any other systemic features, HH is observed in syndromic disorders such as Pallister-Hall syndrome (PHS) and oral-facial-digital syndrome (OFD). Here, we explore the possible involvement of somatic mutations in HH. Methods: We analyzed paired blood and hamartoma samples from 18 individuals, including three with digital anomalies, by whole-exome sequencing. Detected somatic mutations were validated by Sanger sequencing and deep sequencing of target amplicons. The effect of GLI3 mutations on its transcriptional properties was evaluated by luciferase assays using reporters containing eight copies of the GLI-binding site and a mutated control sequence disrupting GLI binding. Results: We found hamartoma-specific somatic truncation mutations in GLI3 and OFD1, known regulators of sonic hedgehog (Shh) signaling, in two and three individuals, respectively. Deep sequencing of amplicons covering the mutations showed mutant allele rates of 7-54%. Somatic mutations in OFD1 at Xp22 were found only in male individuals. Potential pathogenic somatic mutations in UBR5 and ZNF263 were also identified in each individual. Germline nonsense mutations in GLI3 and OFD1 were identified in each individual with PHS and OFD type I in our series, respectively. The truncated GLI3 showed stronger repressor activity than the wild-type protein. We did not detect somatic mutations in the remaining 9 individuals. Interpretation: Our data indicate that a spectrum of human disorders can be caused by lesion-specific somatic mutations, and suggest that impaired Shh signaling is one of the pathomechanisms of HH.
... The other types are extremely rare. 157 The prevalence of oro-facial-digital syndrome type 1 is unknown, but the annual incidence is estimated to be between 1:250 000 and 1:50 000 live births. 158 It is transmitted as an X-linked dominant trait, which occurs mostly in females; the disease has lethal effects in males. ...
Full-text available
A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosa and alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oral signs could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro‐ectodermal dysplasia, dyskeratosis congenita, Ehlers‐Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz‐Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio‐osteo‐hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro‐facial‐digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oral cavity (ie palate, tongue and gingiva). Fordyce′s granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.
... Mutation detection in OFD1 is necessary for definitive diagnosis, especially for genetic counselling, preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis. Fig. 5 demonstrates the frequency of reported OFD1 mutations (6,10,(14)(15)(16)(17)(22)(23)(24)(25)(26)(27)(28)(29)(30). Majority of mutations in OFD1 have been identified in exons 3, 7, 8, 9, 12, 13 and 16, which may represent mutational hotspots. ...
Full-text available
Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene, which can result in embryonic male lethality. In this study, we present a family suffering from orofaciodigital syndrome type I who referred to Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences in 2015. Two female siblings and their mother shared a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 gene. Clinically, the sibling had oral, facial and brain abnormalities, whereas their mother is very mildly affected. She also had history of recurrent miscarriage of male fetus.
Orofaciodigital syndrome type 1 (OFDS1) is a genetic disorder characterized by specific oral, facial, and limb malformations. A 14-month-old girl with congenital cleft palate, lower lip midline cleft, and digital anomalies admitted to our hospital was preliminarily diagnosed with OFDS1. Genetic analysis revealed that she carried a heterozygous variant of OFD1 at locus Xp22.2 on the X chromosome. Herein, we present the specific phenotype and genotype and the treatment modalities for this patient and references for diagnosing and treating OFDS.
Full-text available
The OFD1 protein is necessary for the formation of primary cilia and left–right asymmetry establishment but additional functions have also been ascribed to this multitask protein. When mutated, this protein results in a variety of phenotypes ranging from multiorgan involvement, such as OFD type I (OFDI) and Joubert syndromes (JBS10), and Primary ciliary dyskinesia (PCD), to the engagement of single tissues such as in the case of retinitis pigmentosa (RP23). The inheritance pattern of these condition differs from X‐linked dominant male‐lethal (OFDI) to X‐linked recessive (JBS10, PCD, and RP23). Distinctive biological peculiarities of the protein, which can contribute to explain the extreme clinical variability and the genetic mechanisms underlying the different disorders are discussed. The extensive spectrum of clinical manifestations observed in OFD1‐mutated patients represents a paradigmatic example of the complexity of genetic diseases. The elucidation of the mechanisms underlying this complexity will expand our comprehension of inherited disorders and will improve the clinical management of patients.
Background Primary ciliary dyskinesia (PCD) is a motile ciliopathy, whose symptoms include airway infections, male infertility and situs inversus . Apart from the typical forms of PCD, rare syndromic PCD forms exist. Mutations of the X-linked OFD1 gene cause several syndromic ciliopathies, including oral-facial-digital syndrome type 1, Joubert syndrome type 10 (JBTS10), and Simpson-Golabi-Behmel syndrome type 2, the latter causing the X-linked syndromic form of PCD. Neurological and skeletal symptoms are characteristic for these syndromes, with their severity depending on the location of the mutation within the gene. Objectives To elucidate the role of motile cilia defects in the respiratory phenotype of PCD patients with C-terminal OFD1 mutations. Methods Whole-exome sequencing in a group of 120 Polish PCD patients, mutation screening of the OFD1 coding sequence, analysis of motile cilia, and magnetic resonance brain imaging. Results Four novel hemizygous OFD1 mutations, in exons 20 and 21, were found in men with a typical PCD presentation but without severe neurological, skeletal or renal symptoms characteristic for other OFD1 -related syndromes. Magnetic resonance brain imaging in two patients did not show a molar tooth sign typical for JBTS10. Cilia in the respiratory epithelium were sparse, unusually long and displayed a defective motility pattern. Conclusion Consistent with the literature, truncations of the C-terminal part of OFD1 (exons 16–22) almost invariably cause a respiratory phenotype (due to motile cilia defects) while their impact on the primary cilia function is limited. We suggest that exons 20–21 should be included in the panel for regular mutation screening in PCD.
Orofaciodigital syndrome type I and X‐linked recessive Joubert syndrome are known ciliopathic disorders that are caused by pathogenic variants in OFD1 gene. Endocrine system involvement with these conditions is not well described. We present the first report of a newborn male with a novel hemizygous variant in OFD1 gene c.515T>C, (p.Leu172Pro) resulting in X‐linked Joubert syndrome and orofaciodigital features with complete pituitary gland aplasia and subsequent severe hypoplasia of peripheral endocrine glands. This clinical report expands the phenotypic spectrum of endocrine system involvement in OFD1‐related disorders and suggests that OFD1 gene may be related to pituitary gland development.
Background: OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis. Cases: We report the investigation of three female fetuses in which corpus callosum agenesis was detected by ultrasound during the second trimester of pregnancy. In all three fetuses, fetopathological examination allowed the diagnosis of OFD1 syndrome, which was confirmed by molecular analysis. Conclusions: To our knowledge, these are the first case reports of antenatal diagnosis of OFD1 syndrome in the absence of familial history, revealed following detection of agenesis of the corpus callosum. They highlight the impact of fetal examination following termination of pregnancy for brain malformations. They also highlight the contribution of ciliary genes to corpus callosum development.
Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene, which can result in embryonic male lethality. In this study, we present a family suffering from orofaciodigital syndrome type I who referred to Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences in 2015. Two female siblings and their mother shared a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 gene. Clinically, the sibling had oral, facial and brain abnormalities, whereas their mother is very mildly affected. She also had history of recurrent miscarriage of male fetus.
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Key features of the oral-facial-digital syndrome type 1 (OFD1) include malformations of the face, oral cavity and digits. In addition, the clinical phenotype often includes mental retardation and renal functional impairment. Approximately 75% of cases of OFD1 are sporadic, and the condition occurs almost exclusively in females. In familial cases, the most likely mode of inheritance is considered to be X-linked dominant with prenatal lethality in affected males. Therefore, the OFD1 gene product appears to have widespread importance in organogenesis and is essential for fetal survival. We have studied two kindreds in which the clinical course was dominated by polycystic kidney disease requiring dialysis and transplantation. Using polymorphic chromosome markers spaced at approximately 10 cM intervals along the X chromosome, we mapped the disease to a region on the short arm of the X chromosome (Xp22.2-Xp22.3) spanning 19.8 cM and flanked by crossovers with the markers DXS996 and DX7S105. There was a maximum lod score of 3.32 in an 'affecteds only' analysis using a marker within the KAL gene (theta = 0.0 ), thereby confirming the location of the gene for OFD1 on the X chromosome. The remainder of the X chromosome was excluded by recombinants in affected individuals. The importance of our findings includes the definitive assignment of this male-lethal disease to the X chromosome and the mapping of a further locus for a human polycystic kidney disease. Furthermore, this mapping study suggests a possible mouse model for OFD1 as the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs, maps to the homologous region of the mouse X chromosome.
Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal disease caused by inadequate aspartylglucosaminidase (AGA) activity. The disease is prevalent in the genetically isolated Finnish population. We have used a new method, solid-phase minisequencing, to determine the frequency of two missense mutations in the AGA gene in this population. In samples from 70% of the Finnish AGU families, we found that the two nucleotide changes were always associated, and they were identified in 98% of the AGU alleles analyzed. Thus, the high prevalence of AGU in the Finnish population is the consequence of a founder effect of one ancient mutation. The identification of asymptomatic carriers by the minisequencing test proved to be unequivocal. The method also allowed quantification of a mutated nucleotide sequence present in less than 1% of a sample. The frequency of AGU carriers in this population was 1/36 when estimated by quantifying the mutated AGU allele in a pooled leukocyte sample from 1350 normal Finnish individuals.
Orofaciodigital syndrome type I (OFD I) includes striking orodental, facial, digital, renal, and central nervous system (CNS) abnormalities. Frequently associated with mental retardation, OFD I is inherited as an X-linked dominant trait, lethal in males. Here, we report the variable expressivity of OFD I in 6 black U.S. females and review findings in 2 previously reported black patients. Only these 8 of over 160 reported cases involve blacks. Abnormalities observed in black patients are similar to those observed in whites, but with specific differences. Only 25% of the blacks had cleft palate and none was observed with midline cleft of the upper lip. Among whites, 80% have cleft palate and 45% midline cleft of the upper lip. These findings suggest that racial genetic factors may protect lip and palate development in blacks, even in the presence of the OFD I gene. CNS abnormalities, including agenesis of the corpus callosum, hydrocephaly, cystic brain lesions, seizures, and mental retardation, were present in 50% of our the cases. This figure is greater than previously reported. Polycystic kidneys were present in 3 of our patients. Including a previously reported patient, 50% of the black OFD I patients show polycystic kidneys. Hyperplastic and supernumerary frenula, with or without brachydactyly, have been shown to be strong diagnostic criteria in our patients. New findings reported here include intracranial berry aneurysm, periodontal disease, and lip pits. Clinicians treating these patients should be aware of the pleiotropic manifestations of the syndrome, which may include renal and CNS anomalies. Ultrasonic and computed tomography scan studies are indicated in patients diagnosed with OFD I.
A three generation family with orofaciodigital syndrome type I is described. Several family members had been thought to suffer from autosomal dominant polycystic kidney disease but examination of the proband led to establishment of the correct diagnosis. The genetic implications for the offspring of the affected women and other family members were significantly altered.
We report a female case of orofaciodigital syndrome type I (OFD I) associated with polycystic kidneys and agenesis of the corpus callosum. She had chronic renal failure requiring maintenance dialysis and significant neurological deficits. Her mother had less severe OFD I associated with polycystic kidneys but her renal function was normal and there was no clinical or radiological evidence of a structural abnormality of the brain.
A male infant is described showing all the major features of the oral-facial-digital syndrome (OFD): lobulated tongue with hypertrophic frena, fibrous bands extending into alveolar clefts, pseudocleft of upper lip, cleft palate, hypoplastic alae nasi, dystopia canthorum, various digital anomalies, and typical X-ray appearance of the skull. A partial agenesis of the corpus callosum with a lipoma was indicated by pneumoencephalography and angiography. The OFD syndrome is confined to females. In the present case an XXY chromosome constitution was demonstrated by cytogenetic studies. The occurrence of OFD and Klinefelter's syndrome in one and the same person is ascribed to a very rare coincidence. OFD is considered to be due to an X-linked dominant mutant gene, with a recessive lethal effect. X-linkage is supported by the pattern of a more extreme lethal expression in hemizygous males versus viability of heterozygous females. An XXY individual is viable, presumably because of the normal allele which is active in a fraction of its cells. Other reports of males with OFD are critically evaluated.