Oral-facial-digital syndrome with Y-shaped fourth metacarpals and endocardial cushion defect.

We report on a boy with pseudo-cleft of the upper lip, cleft palate, bifid uvula, lobulated tongue, hypoplasia of the epiglottis, both preaxial and central polydactyly of the hands (Y-shaped fourth metacarpals), bilateral preaxial polydactyly of the feet, postaxial polydactyly of the left foot, hearing impairment, and congenital heart disease with endocardial cushion defect. These clinical manifestations resembled oral-facial-digital syndrome type II (OFDS II, Mohr syndrome) or type VI (Váradi syndrome), associated with an atrioventricular canal. Clinical variability of OFDS II has been observed repeatedly. To the best of our knowledge, this is the first reported case of OFDS II with Y-shaped fourth metacarpals. In addition to Y-shaped fourth metacarpals, Mohr syndrome plus atrioventricular canal and hypoplasia of the epiglottis may represent an additional subgroup of OFDS.     

Orocardiodigital syndrome: an oral-facial-digital type II variant associated with atrioventricular canal.

We report on a patient with a constellation of anomalies including hamartomas of the tongue, polysyndactyly, and atrioventricular canal. A similar association has been previously described by Orstavik et al in two sibs. The clinical spectrum of the oralfacial-digital syndrome (OFDS) type II includes all these features. In particular, congenital heart defect, mainly atrioventricular canal, has been described in a few cases. It has been previously suggested that these latter patients may be affected by a variant of OFDS type II. We propose to distinguish this orocardiodigital variant and point out the association of the syndrome with atrioventricular canal.     

Jeune syndrome with tongue lobulation and preaxial polydactyly,and Jeune syndrome with situs inversus and asplenia: Compound heterozygosity Jeune-Mohr and Jeune-Ivemark?

We report on a male infant with internal hydrocephalus, absence of corpus callosum, papillomas and lobulation of the tongue, notches of the alveolar ridges, short ribs, dysplastic pelvis, hypospadias, short limbs with bowed long tubular bones and postaxial polydactyly of hands, and preaxial polydactyly in one foot. Radiologically this case shares manifestations with Jeune syndrome; the tongue lobulation and the preaxial polydactyly are similar to findings in Mohr syndrome, or short-rib polydactyly syndrome (SRPS), type Majewski. In addition, a female newborn presented with manifestations of Jeune and Ivemark syndromes. One explanation for this overlap may be compound heterozygosity for these syndromes. © 1996 Wiley-Liss, Inc.     

Neuropathologic findings in a case of OFDS type VI (Váradi syndrome)

Oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome is a rare autosomal-recessive disorder distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities. Histopathologic characterization of the cerebellar abnormalities has not been described previously. We describe the neuropathologic findings in a stillborn, 21-week estimated gestational age (EGA) male fetus diagnosed antenatally with signs of OFDS VI. Autopsy findings included: facial abnormalities, postaxial central polydactyly of the right hand, bilateral bifid toes, and absence of cerebellar vermis with hypoplasia of the hemispheric cortex. Microscopic analysis of the cerebellum demonstrated absence of the subpial granular cell layer and disruption or dysgenesis of the glial architecture. These histopathologic findings suggest that a primary neuronal or glial cell defect, rather than an associated Dandy-Walker malformation, may account for the cerebellar abnormalities in this form of oral-facial-digital syndrome. Am. J. Med. Genet. 77:38–42, 1998. © 1998 Wiley-Liss, Inc.     

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands.

We report two unrelated, long surviving patients (2 and 17 years) with syndromal hypothalamic hamartoblastoma. Both showed mild facial dysmorphism (downward slanted palpebral fissures, ptosis, microretrognathia), cleft epiglottis, and developmental delay. The younger child had stenosis of the pulmonary arteries, complex urogenital malformations, and anal atresia. In the oldest patient, the hamartoma caused precocious puberty of the central type, combined with complete hGH deficiency. Both patients showed bony anomalies of the extremities: variable proximal synostosis between central (2nd to 4th) metacarpals or intercalary polydactyly with generalised brachydactyly, severe brachytelephalangism, syndactyly, and nail hypoplasia. Together with the absence of anomalies of cholesterol metabolism, a combination of oral frenula, laryngeal malformations, digestive abnormalities, intercalary polysyndactyly, generalised brachytelephalangism, and nail hypoplasia should allow the delineation of Pallister-Hall syndrome, even when a CNS tumour is absent. The radiological abnormalities are helpful in differentiating Pallister-Hall syndrome from the other syndromes in which hypothalamic hamartoblastoma is observed. This is of major importance for genetic counselling, since Pallister-Hall syndrome may be a dominantly inherited disorder, thus contrasting with most of the other disorders with the CAVE phenotype, which are recessively inherited.     

Acromelic frontonasal "dysplasia": further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome).

We report on a stillborn boy with frontonasal malformation (Sedano-Jiràsek type D-DeMyer type I), associated with encephalocoele, occipital meningocele and preaxial polydactyly of the feet. This form of frontonasal dysplasia was documented previously in a few other cases with various combinations of postaxial polydactyly, tibial hypoplasia, epibulbar dermoid, occipital encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. Most cases are sporadic.     

Acromelic frontonasal “dysplasia”: Further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome)

We report on a stillborn boy with frontonasal malformation (Sedano-J?iràsek type D—DeMyer type I), associated with encephalocoele, occipital meningocele and preaxial polydactyly of the feet. This form of frontonasal dysplasia was documented previously in a few other cases with various combinations of postaxial polydactyly, tibial hypoplasia, epibulbar dermoid, occipital encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. Most cases are sporadic.     

Hypothalamic hamartoma in oral-facial-digital syndrome type VI (Váradi syndrome)

Oral-facial-digital syndrome (OFDS) type VI (Váradi syndrome) is an autosomal recessive trait of orofacial anomalies, cerebellar dysgenesis, and polysyndactyly. Developmental anomalies of the posterior fossa, including cerebellar hypoplasia and variants of the Dandy-Walker complex, are the most common central nervous system malformations reported in patients with this syndrome. We report hypothalamic hamartoma, supernumerary maxillary incisor, and precocious puberty in a boy with OFDS type VI. We propose that hypothalamic hamartoma is an occasional manifestation of OFDS type VI. © 1994 Wiley-Liss, Inc.     

Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome

We report on wide phenotypic variations within a family with SALL1 mutations; the elder sister presented with a Townes-Brocks syndrome phenotype including external ear anomalies, preaxial polydactyly, and anteriorly placed anus, whereas the younger sister presented with a phenotype resembling Goldenhar syndrome, including atretic ear canals, mandibular hypoplasia, and right preaxial polydactyly as well as an epibulbar dermoid. The mother had abnormal external ears but was otherwise structurally normal, and the father was asymptomatic. Analysis of the SALL1 gene revealed that both daughters were heterozygous for nonsense mutation 1256T>A (L419X), that is present 5' to the region encoding the first double zinc finger. The mother was heterozygous for the L419X mutation. The younger daughter is the first patient with a SALL1 mutation to exhibit a classic Goldenhar syndrome-like phenotype with an epibulbar dermoid. The observation lends further support to the concept that Goldenhar syndrome is an etiologically heterogeneous disorder that may have a genetic basis in some cases.     

Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36

Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10 000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36.
In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36.
Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.


Keywords: preaxial polydactyly; chromosome 7q36; localisation     

Syndrome of polydactyly,cleft lip,lingual hamartomas,renal hypoplasia,hearing loss,and psychomotor retardation: variant of the Mohr syndrome or a new syndrome?

Three sibs, the proband and two monozygotic twins, have a condition including mental retardation, postnatal somatic retardation, preaxial polydactyly of the feet, bifid third metacarpal, median cleft lip, fatty hamartomas on the dorsum of the tongue, conductive hearing loss, and unilateral or bilateral renal agenesis. This probably autosomal recessive syndrome could be a further example of the condition described by Váradi et al or a variant of the Mohr syndrome.     

Cardiac malformations in patients with oral-facial-skeletal syndromes: Clinical similarities with heterotaxia

Oral-facial-skeletal (OFS) syndromes include short rib–polydactyly (SRP) and oral-facial-digital (OFD) syndromes. Congenital heart defect (CHD), mainly atrioventricular canal defect (AVCD), is a cardinal finding in the Ellis–van Creveld (EVC) syndrome, but it occurs only occasionally in other SRP and OFD syndromes. The cardiac characteristics of all patients with OFS syndromes evaluated at our hospital from January 1986 to April 1997 were analyzed and compared with published reports. Ten patients with EVC syndrome, one with McKusick-Kaufman syndrome, and one with OFD syndrome type II had AVCD. Eight patients (67%) had a common atrium, eight (67%) a persistent left superior vena cava (LSVC) draining into the left atrium because of an unroofed coronary sinus in five (42%), and left-sided obstructive lesions in three (25%). One patient with EVC syndrome had AVCD, common atrium, double outlet right ventricle, persistent LSVC associated with “asplenia syndrome,” visceral heterotaxia, and right isomerism. The combination of CHDs found in the personal series of OFS syndromes suggests pathogenetic similarity with heterotaxia syndromes. Published results also corroborate the association between OFS syndromes and CHDs usually occurring in heterotaxia. Molecular studies could shed light on the genetic mechanisms implicated in the cause of the OFS and heterotaxia syndromes. Am. J. Med. Genet. 84:350–356, 1999. © 1999 Wiley-Liss, Inc.     

GLI3‐related polydactyly: a review

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3‐related polydactyly are discussed first. This is followed by a detailed review of the genotype–phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3‐related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV‐Greig‐acrocallosal spectrum, postaxial polydactyly types A/B, Pallister–Hall syndrome (PHS), and oral‐facial‐digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term ‘Forme Fruste’ preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.     

Oral-facial-digital syndrome type IX in a patient with Dandy-Walker malformation.

We report a girl with oral, facial, and digital anomalies including multiple alveolar frenula, lobulated tongue with nodules, a posterior cleft palate, hypertelorism, a prominent forehead with a large anterior fontanelle, and postaxial polydactyly in both hands and the right foot, features compatible with the oral-facial-digital syndrome (OFDS). In addition, she had bilateral microphthalmia, optic disc coloboma, and retinal degeneration with partial detachment, thus establishing a diagnosis of OFDS type IX. Dandy-Walker malformation and retrobulbar cysts were observed on MRI. These additional malformations have not been reported in OFDS type IX. The frequent apnoeic spells which occurred immediately after birth were relieved after cystoperitoneal shunt implantation for hydrocephalus. Considering our case and previous reports of OFDS type IX, including two male sibs, a boy born to consanguineous parents, and three females, inheritance is probably autosomal recessive.     

Absent pituitary gland and hypoplasia of the cerebellar vermis associated with partial ophthalmoplegia and postaxial polydactyly: a variant of orofaciodigital syndrome VI or a new syndrome?

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.     

Femoral hypoplasia-unusual facies syndrome with bifid hallux, absent tibia, and macrophallus: a report of a Bedouin baby.

A male Bedouin baby with the clinical profile of femoral hypoplasia-unusual facies syndrome is described. The phenotype includes bilateral asymmetrical lower limb hypoplasia/aplasia with short remnants of both femora, absent right tibia, bifid right big toe, dysmorphic facies, thoracic/pelvic abnormalities, macrophallus, and bilateral cryptorchidism. This report re-emphasises the previously described rare association of femoral hypoplasia-unusual facies syndrome with preaxial polydactyly and suggests that the clinical spectrum of the syndrome could be stretched further to accommodate other unusual traits, for example, macrophallus and absent tibia.     

Holoprosencephaly-polydactyly (''pseudotrisomy 13'') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study.

A syndrome of holoprosencephaly and postaxial polydactyly, associated with hydrocephalus, heart defect, adrenal hypoplasia, and other visceral malformations, has been observed in five unrelated children with normal chromosomes. Clinical overlap with lethal acrodysgenital dwarfism (Smith-Lemli-Opitz syndrome type II) and hydrolethalus syndrome is discussed. Recessive inheritance seems likely.     

Sibs with anencephaly, anophthalmia, clefts, omphalocele, and polydactyly: hydrolethalus or acrocallosal syndrome?

Major characteristics of the acrocallosal syndrome include severe mental retardation, agenesis or hypoplasia of the corpus callosum, and polydactyly of fingers and toes. In the past few years, anencephaly has also been noted, together with other midline defects. We report on a nonconsanguineous, Norwegian couple with a history of two pregnancies with a male and a female fetus, respectively, with anencephaly, median cleft lip and palate, omphalocele, and preaxial polydactyly, suggesting the diagnosis of the acrocallosal syndrome. Both fetuses also lacked eyes and nose, a finding not previously reported in the acrocallosal syndrome. Microphthalmia has been reported in the hydrolethalus syndrome, which may be caused by mutations in the same gene as the acrocallosal syndrome. The present report adds support to the hypothesis that the acrocallosal and hydrolethalus syndromes may be allelic conditions. The family history is consistent with autosomal recessive inheritance.     

Bilateral preaxial polydactyly in a WAGR syndrome patient

We report on a 30-month-old baby girl with typical clinical features of WAGR syndrome. In addition, the patient showed bilateral preaxial polydactyly of the feet. Cytogenetic and fluorescent in situ hybridization (FISH) analyses identified a deletion, del(11)(p13p14.1), extending from 6.1 to 21.7 Mb in size. Although the simultaneous appearance of WAGR and polydactyly has been already described, to our knowledge this is the first case in which the characterization at the cytogenetic molecular level of a patient with these phenotypes is reported. These observations indicate that preaxial polydactyly may be another feature of the WAGR syndrome and suggest the existence of a related gene in the WAGR critical region or in its proximity.     

Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I

Human GLI3 gene mutations have been identified in several phenotypes of digital abnormality such as Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type-IV (PPD-IV) and postaxial polydactyly. However, the different phenotypes resulting from GLI3 mutations have not yet been properly defined. We have experienced two types of digital abnormality without other complicating developmental defects; a family with foot PPD-IV with syndactyly of the third and fourth fingers, and four sporadic cases with biphalangeal thumb polydactyly (PPD-I). The genes responsible for syndactyly of the third and fourth fingers (syndactyly type-I) and PPD-I have not yet been identified; we therefore examined the involvement of the GLI3 gene in these subtypes of digital abnormality. We found a non-sense mutation in the GLI3 gene in the family with foot PPD-IV accompanied with hand syndactyly of the third and fourth fingers, but no mutations were detected in the GLI3 gene in the four other cases with PPD-I alone. Thus, the phenotype of foot PPD-IV accompanied with hand syndactyly of the third and fourth fingers may result from a GLI3 mutation, whereas the PPD-I phenotype alone is not caused by GLI3 gene defect. These results will help to define the phenotypic spectrum of GLI3 morphopathies, which have been recently proposed.