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.     

Meckel Gruber Syndrome--a case report

Meckel Gruber Syndrome is a rare syndrome inherited as Mendelian autosomal recessive condition. The affected infant usually has a large occipital encephalocoele associated with renal cysts and sometimes polydactyly. The prognosis is poor. The affected child is still born or dies early in infancy. If diagnosis is done by prenatal ultrasound examination termination of pregnancy can be done.     

“Holoprosencephaly-polydactyly” (pseudotrisomy 13) syndrome: Expansion of the phenotypic spectrum

Analysis of familial cases of the so called “holoprosencephaly-polydactyly” (“pseudotrisomy 13”) syndrome shows that neither holoprosencephaly, nor polydactyly are obligatory manifestations of this condition. This review of previous case report shows that each of these anomalies is only found in approximately 60% of affected sibs, and therefore these sentinel abnormalities are not required for diagnosis. We propose a widening of the phenotypic spectrum of this syndrome and consideration of the use of an eponomic name, such as the Cohen-Gorlin syndrome, or clear recognition that the sentinel findings of holoprosencephaly and polydactyly are not essential for diagnosis. We propose the following diagnostic criteria for the syndrome. The diagnostic criteria for sporadic cases would include a normal karyotype and either (1) a combination of holoprosencephaly and postaxial polydactyly with or without other characteristics, or (2) a combination of holoprosencephaly with other characteristics but without polydactyly, or (3) a combination of postaxial polydactyly, brain defects (microcephaly, hydrocephaly, agenesis of corpus callosum) and other characteristics. The diagnostic criteria for the familial cases would be the same, except that, as long as the other sibs have no abnormalities contradicting the diagnosis, a normal karyotype would be required in only one affected sib. © 1993 Wiley-Liss, Inc.     

Cystic dysplastic kidneys associated with Dandy-Walker malformation and congenital hepatic fibrosis. Report of two cases

The combined abnormalities of Dandy-Walker malformation, congenital hepatic fibrosis, and generalized cystic dysplastic kidneys were found in two sanguineously unrelated premature babies. This type of cerebrohepatorenal malformation is certainly unique and is generally diagnosed based on the characteristic renal lesion. Remarkably, similar renal lesions have been found in Meckel's syndrome, Goldston's syndrome, and Miranda's syndrome. The present cases can be distinguished from Meckel's syndrome on the basis of the presence of Dandy-Walker malformation and the absence of polydactyly and occipital meningoencephalocele. Although the authors' cases resemble the latter two syndromes in terms of the presence of Dandy-Walker malformation, it is tentatively considered that the distinct triads found in the present cases could represent a new variant of a multiple malformation syndrome with generalized cystic dysplastic kidneys. The etiology of these cases remains unclear, but a genetic factor, which has been suggested as for other syndromes, might be involved.     

Dandy-Walker malformation in the Meckel syndrome

The Meckel syndrome (MS) is an autosomal recessive disorder classically defined by the triad of occipital encephalocele, multicystic kidneys, and polydactyly. Here we describe 3 sibs with varying manifestations of MS. The propositus had isolated cystic renal disease. The other sibs were both prenatally diagnosed with renal disease, polydactyly, and the Dandy-Walker malformation, an unusual central nervous system defect in MS. These findings are discussed in the context of the phenotypic expression of MS and the nosology of this disorder and the cerebro-reno-digital (Meckel-like) syndromes. © 1995 Wiley-Liss, Inc.     

Familial acromelic frontonasal dysostosis: autosomal dominant inheritance with reduced penetrance

Acromelic frontonasal dysostosis (AFND) represents a subgroup of patients with frontonasal malformation with limb abnormalities including preaxial polydactyly and tibial hypoplasia. Previous case reports have suggested autosomal recessive inheritance, given parental consanguinity. However, no affected siblings have been described. Longitudinal clinical history is limited as many do not survive the first years of life. The molecular basis of AFND is not known. Previous investigators have proposed that AFND may result from a perturbation in the Sonic Hedgehog pathway. We present clinical and radiographic findings in two unrelated boys, ages 8 and 9 years, with AFND, one of whom has a family history suggesting dominant inheritance. A focused study of genetic marker data and candidate gene mutation analysis in this family is presented.     

Coloboma,mental retardation,hypogonadism, and obesity: Critical review of the so-called Biemond syndrome type 2, updated nosology,and delineation of three “new” syndromes

Biemond syndrome type 2 (BS2) is classically regarded as a recessively inherited condition (MIM 210350) comprising mental retardation, coloboma, obesity, polydactyly, hypogonadism, hydrocephalus, and facial dysostosis. Clinically, the disorder is closely related to Bardet-Biedl syndrome. Few cases have been reported, most of them before 1970. We present clinical data on three mentally retarded sporadic cases with coloboma, obesity, and hypogenitalism (in two of them), fitting at first glance a diagnosis of BS2. A review documents striking clinical variability among the patients said to have BS2. We propose a new nosology of those cases and delineate several new clinical forms. Purported BS2 cases may be divided into: (1) Bardet-Biedl syndrome with fortuitous coloboma or aniridia, (2) BS2 sensu stricto, a recessively inherited syndrome of sexual infantilism, short stature, coloboma, and preaxial polydactyly without obesity, only known from the original report, (3) a “new” dominantly inherited form of colobomatous microphthalmia occasionally associated with obesity, hypogonadism, and mental retardation, to which our observations belong, (4) cytogenetically proven Rubinstein-Taybi syndrome (one case), (5) an unclassifiable, early lethal familial syndrome resembling Buntinx-Majewski syndrome, and (6) a “new” coloboma-zygodactyly-clefting syndrome. The latter two syndromes may result from chromosomal anomaly. Am. J. Med. Genet. 69:370–379, 1997. © 1997 Wiley-Liss, Inc.     

Frontonasal dysplasia in the Klippel-Feil syndrome: A new associated malformation

This paper describes an 8-year-old girl with Klippel-Feil syndrome (KFS) associated with frontonasal dysplasia, Sprengel deformity and postaxial polydactyly. These findings are tentatively explained on the basis of a single mutant gene for KFS with broad action in the morphogenesis of the skeletal system.     

Skeletal malformations in fetuses with Meckel syndrome

In six fetuses with Meckel syndrome (gestational age 16–23 weeks, crown-rump length 130–170 mm) the skeleton was examined as part of the autopsy procedure using whole body radiography and special radiographic techniques. In the upper and lower limbs we found similar types of polydactyly. We noted four types, based on the number and morphology of metacarpals and metatarsals. In the individual fetus there was more often similarity in the pattern of malformation in the two hands or in the two feet than there was between the pattern of malformation seen in the hands and that seen in the feet. Only one foot was normal. Malformations of the cranial base (the basilar part of the occipital bone or the postsphenoid bone) occurred in five cases, and the vertebral bodies in the lumbar region of the spine were malformed (cleft) in three cases. It is proposed that a skeletal analysis be included in the future evaluation of phenotypes in Meckel syndrome. Am. J. Med. Genet. 84:469–475, 1999. © 1999 Wiley-Liss, Inc.     

Fronto-nasal dysostosis,callosal agenesis,crossed-fused ectopia,tibial hemimelia,and preaxial polydactyly of feet: Severe expression of the acrocallosal syndrome?

We report on a girl with frontonasal “dysostosis,” callosal agenesis, crossed-fused ectopia, tibial hemimelia, and preaxial polydactyly of feet. This pattern of the developmental defects suggests a severe form of the acrocallosal syndrome. Implications for genetic counselling are discussed. © 1993 Wiley-Liss, Inc.     

Phenotypic variability in Meckel–Gruber syndrome

Five Bedouin sibs are described with Meckel-Gruber syndrome (MGS), an autosomal recessive disorder with multiple abnormalities. Each affected sib manifested only two of the three cardinal signs of MGS: occipital encephalocele and polycystic kidneys, lacking polydactyly. The phenotypic variability of the MGS pleiotropic gene is briefly discussed.     

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.     

A “new” lethal multiple congenital anomaly syndrome: Joint contractures,cerebellar hypoplasia,renal hypoplasia,urogenital anomalies,tongue cysts,shortness of limbs,eye abnormalities,defects of the heart,gallbladder agenesis,and ear malformations

Three cases of a lethal malformation syndrome with severe visceral anomalies were seen in two families and include one pair of sibs. The predominating external manifestations are mesomelic dwarfism, micrognathia, V-shaped upper lip, microglossia, thick alveolar ridges, ambiguous genitalia, webbed neck, highly arched palate, clubfeet, fused fontanelles, inclusion cysts of the tongue, four-finger creases, digital anomalies, apparently low-set ears, widely spaced nipples, and dislocated thighs and forearms. The internal findings include oligopapillary renal hypoplasia, severe congenital heart defect, cerebellar hypoplasia, pulmonary hypoplasia, hypoplastic larynx, and hypoplastic gallbladder. Other findings from the two autopsies and one clinical investigation not documented in all three patients include unilobar lungs, hydrocephalus, cataracts, microphthalmia, polydactyly, islet cell hyperplasia, suprapubic skin crease, urethral anomalies, and a decreased number of turns of the cochlea. The hypoplasia seen in the several affected organs is similar to the disordered development seen in experimental models of branching epithelial morphogenesis in which mesenchymal-epithelial interaction has been disrupted.     

Skeletal malformations in fetuses with Meckel syndrome.

In six fetuses with Meckel syndrome (gestational age 16-23 weeks, crown-rump length 130-170 mm) the skeleton was examined as part of the autopsy procedure using whole body radiography and special radiographic techniques. In the upper and lower limbs we found similar types of polydactyly. We noted four types, based on the number and morphology of metacarpals and metatarsals. In the individual fetus there was more often similarity in the pattern of malformation in the two hands or in the two feet than there was between the pattern of malformation seen in the hands and that seen in the feet. Only one foot was normal. Malformations of the cranial base (the basilar part of the occipital bone or the postsphenoid bone) occurred in five cases, and the vertebral bodies in the lumbar region of the spine were malformed (cleft) in three cases. It is proposed that a skeletal analysis be included in the future evaluation of phenotypes in Meckel syndrome.     

Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.     

Prenatal diagnosis of Smith–Lemli–Opitz syndrome,type II

Smith–Lemli–Opitz syndrome, type II (SLOS-II) is a severe autosomal recessive disorder characterized by a distinctive face, unusual cleft palate, postaxial polydactyly, congenital heart defects, renal anomalies, and male pseudohermaphroditism. We present the first report of prenatal diagnosis of SLOS-II, as well as an additional report of prenatal detection of multiple anomalies, in which a positive diagnosis of SLOS II was made postanatally. In neither case was the pregnancy known prospectively to be at risk for SLOS-II. In the former case, targeted sonographic examination at 31 weeks of gestation showed intrauterine growth retardation, atrioventricular septal defect, mesomelic shortening of the arms, small kidneys, overlapping fingers, and female external genitalia; a 46,XY chromosome constitution had been ascertained previously. A provisional diagnosis of SLOS-II was made prenatally. In the latter case, targeted sonographic examination at 18 weeks of gestation showed severe oligohydramnios, atrioventricular septal defect, and Dandy–Walker malformation. The kidneys and bladder were not visualized. The chromosome constitution was 46,XX. The diagnosis of SLOS-II was made postnatally. In both cases, additional findings compatible with SLOS-II were noted postnatally. Prenatal detection of congenital heart defects and renal abnormalities, in combination with certain additional findings (most notably, female external genitalia in the presence of a 46,XY karyotype, polydactyly, disproportionately short limbs, or intrauterine growth retardation) and a normal karyotype, suggests the diagnosis of SLOS-II, and warrants further investigation. © 1994 Wiley-Liss, Inc.     

Prenatal diagnosis of the Meckel syndrome

Prenatal diagnosis of the Meckel syndrome was made at 20 weeks of gestation from the findings of a biparietal diameter smaller than expected for gestational age, a grossly raised amniotic fluid alphafetoprotein level and a rapid growth of foetal macrophages after 20 hours culture. Termination at 23 weeks of gestation resulted in a male foetus with an occipital encephalocele, microcephaly, polydactyly, and bilateral polycystic kidneys. This case report emphasies the importance for genetic counselling of delineating the Meckel syndrome from the multifactorial cases of neural tube defects, and also illustrates, at least in some cases, that the syndrome can be diagnosed in utero.     

Meckel syndrome.

Meckel syndrome (MKS) is a lethal syndrome with a central nervous system malformation, usually occipital meningoencephalocele, bilaterally large multicystic kidneys with fibrotic changes of the liver, and polydactyly in most cases. Additional anomalies are frequent. A common characteristic of the parenchymal changes of many organs is a proliferation of the stromal connective tissue and increase and dilatation of the associated epithelial ducts. Autosomal recessive inheritance is well confirmed and the gene locus has been mapped to chromosome 17q21-24 by genome wide linkage study. The locus was later refined to within a less than 1 cM region (17q22), in which most of the Finnish MKS patients share a common chromosomal haplotype suggesting one major and relatively old mutation. However, in most of the non-Finnish MKS families studied, this linkage could not be confirmed. The linkage studies provide evidence that more than one locus is involved in bringing about the combination of CNS malformations, cystic kidneys, and polydactyly, maybe even in typical cases of MKS. Prenatal diagnosis of MKS by vaginal ultrasound scan is possible from 11-12 weeks of pregnancy, especially in families where there is a known risk. In those families where linkage to 17q22 is established, prenatal diagnosis by DNA analysis is possible.     

Dandy-Walker malformation and polydactyly: a possible expression of hydrolethalus syndrome

Hydrolethalus syndrome consists of hydrocephalus, polydactyly, micrognathia, midcranial malformations, visceral abnormalities and perinatal lethality. It was first described in Finland, and only a few other cases outside Scandinavia are known. We report the first Hungarian patient who displayed many signs of the syndrome but had no cleft lip and visceral abnormalities. This observation suggests the existence of oligosymptomic hydrolethalus syndrome, and suggests that Dandy-Walker malformation with polydactyly may be a manifestation of the hydrolethalus syndrome.