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We present a girl and autopsy finding of her sister with Mohr-Majewski syndrome (Orofaciodigital syndrome type IV). The parents were first cousins and their two sons died of similar findings. The only healthy child of the family was mildly effected from this syndrome who had cleft palate. These features show the heterogenity of the syndrome.
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INTRODUCTION: In 1978 the authors studied a male gypsy child with a multiple malformation syndrome. In this gypsy colony further five cases were found with similar features. The characteristic syndrome was published in 1980. Subsequently, the syndrome has been quoted as Váradi-Papp syndrome. AIM: To present the 25-year follow-up of this multiple malformation syndrome. RESULTS: The most common features of 29 affected children with this syndrome consists of orofacial (facial dysmorphism, cleft lip and/or palate abnormality, lingual nodule or tumor of the tongue, buccoalveolar frenula, alveolar and dental abnormalities, strabismus), cerebral/cerebellar (deformation of the skull, semilobar holoprosencephaly and/or absence or dysgenesis of cerebellar vermis or corpus callosum or hypothalamus or pituitary gland), digital (metacarpal abnormalities with central polydactyly, reduplication of the big toes) and genital (cryptorchidism, micropenis) anomalies. The patients are growth-retarded and when survival occurs psychomotor retardation is present. Accumulation of consanguinity and because of the involvement of multiple siblings in these families supports the autosomal recessive inheritance. CONCLUSION: Fetal Váradi-Papp syndrome using ultrasonography in the mid-trimester both in routine screening and detailed scanning can be detected, and termination of pregnancy can be offered to the parents.
The orofaciodigital syndromes (OFDS) represent a spectrum of anomalies of the palate, cranium, hands, and feet. Váradi syndrome, designated OFDS type VI, is a rare disorder that is additionally characterized by cerebellar anomalies. The following report is of a patient with OFDS VI and characteristic multiple midline defects: median cleft lip and palate, lingual cleft with nodules, and midline brain malformation. In addition, this case is uniquely associated with the presence of midline (metopic and sagittal) craniosynostoses as well. It is unusual that deformities which result from premature fusion of cranial vault sutures would appear synchronously in a syndrome based on the concept of failure of fusion or coalescence of facial growth centers. The midline represents an independent developmental field, whereby CNS defects and midline anomalies can present concurrently.
Mohr's syndrome consists of an association of three types of malformation : oral, facial, and digital. It is very similar, therefore, to the syndrome of Papillon-Léage and Psaume. Apart from this, precise, constant characteristics can be recognized which identify it as a separate entity. Firstly, the genetic mode of transmission differs. Secondly, clinical signs are dominated by the frequency and severity of the distal lesions, such that bilateral syndactyly of the big toe is a key element in the differential diagnosis.
We report on an infant girl with hydrops, macrocephaly, high forehead, flat face, hypertelorism, broad nasal bridge, median cleft lip and alveolar ridge, grooved palate, accessory frenula, small tongue, milia, severe rib and limb shortness, brachydactyly, talipes equinovarus, Dandy-Walker malformation, accessory spleen, unfixed mesentery, ectopic pancreas, and renal cysts. This patient resembles seven previously reported patients with the Beemer-Langer syndrome, a distinct lethal short rib syndrome characterized by hydrops, markedly short ribs and limbs, median cleft lip with or without cleft palate, flat face, and macrocephaly. Polydactyly is usually absent. Our patient's oral anomalies suggest an orofaciodigital syndrome, but the severe rib and limb shortness distinguish it from those disorders.
Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.
Orofaciodigital syndromes (OFD) are a group of diseases classified according to the phenotype and the mode of inheritance. We report on a fetus presenting with some features of the OFDs but with additional global cerebral dysgenesis. Ultrasonography at 19 weeks of pregnancy disclosed hypoplasia of the cerebral hemispheres with a large intrahemispheric cyst, as well as dysmorphic facial features and brachy-syndactyly IV-V. Fetal brain MRI confirmed these features and disclosed additional morphological anomalies: Agenesis of the vermis, complete agenesis of the corpus callosum, pachygyria of the left hemisphere. Pathological examination showed a disproportionate fetus with large head and short limbs. Dysmorphic features included hypertelorism, broad nasal root, long philtrum, severe micrognathia, microstomia, cleft palate, and lobulated tongue. Radiographs showed distal malformations of the four limbs. Neuropathological examination showed a severe disturbance of the architecture of both hemispheres, more severe on the right side, with four cystic structures located between the hemispheres. Olfactory stalks, mammillary bodies, and midline structures were absent. Cerebellum and brainstem were hypoplastic. On the right hemisphere as on most part of the left one, microscopic findings displayed a complete disruption of the developing mantle with disturbance of the neuronal migration. The present fetus fulfilled the diagnosis of OFD syndrome: Dysmorphic features, cleft palate and lobulate tongue and polysyndactylies of the feet and hands. The cerebral involvement would make it closer to OFD type VI, but brain malformations were far more severe in the present case, with complex and generalized cortical dysgenesis, evoking a disturbance occurring at a very early stage of the embryogenesis.
The orofaciodigital syndromes are a group of possibly seven different malformation syndromes including oral, facial, and digital malformations. Type I has X linked dominant inheritance whereas the other types show autosomal recessive inheritance. An exact diagnosis is therefore important for genetic counselling. We here report a girl with orofaciodigital syndrome type I. She had cystic kidney disease at the age of 8 months which has not previously been reported in an infant with orofaciodigital syndrome. In addition she had unilateral tibial pseudarthrosis which has only rarely been reported in the orofaciodigital syndromes and in type II only.
Orofaciodigital syndrome I is a syndrome, which affects the maxillofacial region. Abnormally developed vestibular frenulum, cleft tongue, asymmetric cleft palate, pseudocleft of the upper lip and hypoplasia of the nasal cartilages are some of the other features. There are some malformations in foot and hand fingers and also mild mental deficiency is present. OFD I syndrome follows an chi-linked dominant mode of transmission trait limited to females and lethal in males. Because of the esthetic and functional manifestations in the maxillofacial region, the syndrome has great importance for pediatric dentistry.
The AA. behaving the orofaciodigital syndromes, describe the main peculiarity of the etiology, anatomo-pathology, clinical features, diagnosis to the light of the late acquisitions about these.
A female patient with orofaciodigital syndrome type I associated with pachygyria, heterotopic gray matter, interhemispheric cyst, agenesis of the corpus callosum, and a Dandy-Walker anomaly is reported. Because some of these defects have been described in patients with different types of orofaciodigital syndromes, we recommend caution when using neuroradiologic criteria to separate these syndromes. Given the severe spectrum of brain abnormalities displayed by our patient, and considering their similarity with the brain defects formerly described in other X-linked dominant conditions with male lethality localized to Xp22, the use of DNA probes from Xp22 is advised in identifying the gene(s) causing orofaciodigital syndrome type I.
We describe a three generation family with three females showing minor features of orofaciodigital syndrome type I and a severely affected male in the third generation. In addition to the classical features of OFD I, the male had bilateral duplication of the halluces, a feature diagnostic of OFD II, and an atrioventricular septal defect. Heart defects have not previously been reported in OFD I but have been reported in OFD II. It is important to examine the mothers of all male neonates with orofaciodigital syndrome with care before making a diagnosis of OFD II.
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.
Three families affected by the rare genetic disorder orofaciodigital syndrome, type I (OFD-1) were screened by computed tomography (CT) to determine the presence of cysts in the kidneys and liver, an association known to occur but not previously described in the radiologic literature. Renal cystic changes in four females with oral, facial, and digital malformations were variable and not distinguishable from other inherited cystic kidney diseases. One patient had biliary ectasia and hepatic cysts. "Polycystic" kidneys occurring only in female members of a family should suggest OFD-1, an X-linked dominant disorder that is lethal in utero in males. Patients known to have the syndrome should be screened for cystic renal disease.
We report two sibs with features overlapping those of orofaciodigital syndrome type VI (Varadi syndrome). Both presented at birth with oculomotor abnormalities, dysmorphic facial features, and dysgenesis of the cerebellar vermis. There were minimal oral manifestations (high arched palate) in both of them and one had postaxial polydactyly of both hands and one foot. In addition, there was evidence of aplasia of the pituitary gland on MRI scan in both of them with evidence of hypopituitarism. Both responded well to hormone replacement therapy with improvement in their linear growth and mental ability. These cases may represent a new autosomal recessive midline defect syndrome with features overlapping OFDS VI. Alternatively the features in these children could represent variability within OFDS VI.
We present a male infant with hypertelorism, median pseudo-cleft of the upper lip and cleft palate, lobulated tongue, hypoplastic larynx and epiglottis, mesomelic shortening of limbs with particularly short and broad tibiae, polydactyly of the upper limbs, severely hypoplastic external genitalia with anorchidism, anal atresia, severe congenital heart defect, and renal agenesis. These features show considerable overlap with severe Majewski type short rib-polydactyly syndrome and so expand the known spectrum of anomalies in orofaciodigital syndrome type IV.
An additional family with the orofaciodigital syndrome. Type I, is presented. On the basis of previously published pedigrees, as well as the present case, data are presented that conclusively support an X-linked dominant mode of inheritance. Segregation analysis demonstrated that not only is there lethality in the male but there is significant lethality in the female due to lyonization. In addition, a review of the familial cases will demonstrate a large degree of intra- and interfamilial variation.