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PubMed2003

Feingold syndrome: clinical review and genetic mapping.

Feingold syndrome is characterized by autosomal dominant inheritance of microcephaly and limb malformations, notably hypoplastic thumbs, and clinodactyly of second and fifth fingers. Syndactyly frequently involves the second and third, as well as the fourth and fifth toes. Approximately one in three Feingold syndrome patients have esophageal or duodenal atresia or both. Anal atresia has been reported in a single case. At least 79 patients in 25 families have been reported. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Vertebral anomalies, cardiac malformations, and deafness have been noted in a minority of patients. Here, we report a patient with hydronephrosis of one kidney and cystic dysplasia of the other, necessitating nephrectomy. The overall pattern of malformations in Feingold syndrome shows considerable overlap with the VATER/VACTERL association. The gene for Feingold syndrome maps to 2p23-p24, but remains to be identified. Comparison of the pattern of anomalies that occurs in the Feingold syndrome in humans and malformations that are present in mice with mutations of genes in the sonic hedgehog signaling pathway suggest, that the elusive Feingold syndrome gene may involve this signaling pathway as well.

Chromosome Mapping↗
PubMed2003

Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis. It is caused by mutations in the gene encoding the enzyme 7-dehydrocholesterol Delta7-reductase (DHCR7), which catalyzes the final step in cholesterol biosynthesis, usually resulting in cholesterol deficiency. We report a 3.5-year-old girl who has cognition in the low average range and normal behavior, but in whom molecular studies identified two missense mutations in DHCR7: V326L and F284L. She was born at term following an uncomplicated pregnancy and delivery, and presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. On physical examination she had mild ptosis, a long philtrum, mild micrognathia, a short, upturned nose, and subtle 2,3 syndactyly. Her 7-dehydrocholesterol (7-DHC) level was markedly elevated at 8.7 mg/dl (normal 0.10 +/- 0.05), and her cholesterol level was normal at 61 mg/dl (normal for newborn period 50-80 mg/dl). Karyotype analysis was normal, 46,XX. Breast milk feeding was initiated and continued for 18 months. Cholesterol supplementation was implemented at 100 mg/kg/day at 3 months, which resulted in increased cholesterol levels and reduced dehydrocholesterol levels. Neuropsychological testing has shown functioning in the low average range, between the 14th and 18th centiles when compared to peers. This is markedly higher than most children with SLOS. She has no behavioral problems. MRI and MRS testing of the brain revealed no structural abnormalities. This is in contrast to a recently reported case by Prasad et al. [2002: Am J Med Genet 108:64-68] with a mild phenotype, behavioral problems, and abnormal MRI, who is compound heterozygote for both a null and missense mutation. Our case suggests that patients with severe feeding disorders with or without Hirschprung disease and postnatal onset microcephaly may warrant screening for SLOS.

Behavior↗
PubMed2004

Macrocephaly-cutis marmorata telangiectatica congenita: report of six new patients and a review.

We report on six additional patients with macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC; MIM 602501) and review the literature. This syndrome is a multiple congenital anomalies/mental retardation and overgrowth disorder comprising macrocephaly, cutis marmorata, vascular marks of lip and/or philtrum, syndactyly, hemihypertrophy, CNS anomalies, and developmental delay. Based on the findings in our 6 patients and on 69 patients previously reported we listed the very frequent (observed in >75%), frequent (25-75%), and less frequent (>25%) components of the syndrome.

Abnormalities, Multiple↗
PubMed2005

A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma.

Oculo-dento-digital dysplasia (ODDD, OMIM no. 164210) is a pleiotropic disorder characterized mainly by ocular anomalies, varying degrees of finger and toe syndactyly, and enamel defects. It is caused by missense mutations in the gene coding for the gap junction protein connexin 43 or GJA1. Other types of mutations have so far not been reported. Here we describe a Dutch kindred with ODDD showing a new symptom, palmoplantar keratoderma, and associated with a novel 2-bp deletion mutation of GJA1. The dinucleotide deletion 780_781delTG is located in the cytoplasmic C-terminal loop and leads to a frameshift. This is predicted to lead to the production of a slightly truncated protein with 46 incorrect amino acids in the C-terminal cytoplasmic loop (C260fsX307). This novel mutation may explain the presence of skin symptoms.

Abnormalities, Multiple↗
PubMed2005

Recurrent adjacent-2 segregation of a familial t(14;21)(q11.2;q11.2): phenotypic comparison of two brothers and a paternal aunt inheriting the der(14).

A 14-year-old boy was referred for a genetics evaluation after high-resolution chromosome analysis showed a small amount of extra material in the proximal long arm of chromosome 21. Five years prior, his karyotype analysis was interpreted as normal with a variant chromosome 21. The patient has short palpebral fissures, strabismus, flat antihelices of the ears, long thumbs with bilaterally absent interphalangeal creases, proximal bilateral 3/4 syndactyly, small testes, hypotonia, mental retardation, and speech problems. He has significant depression and behavioral problems including hyperactivity, aggression, and impulsivity. His 8-year-old brother has more severe behavioral disturbances and depression, but less significant mental retardation. A paternal aunt has mental retardation, is unusually docile, and appears similar to our patient. Chromosome analysis and fluorescence in situ hybridization (FISH) whole chromosome paint of chromosome 21 showed that the patient's father carries a "cryptic" balanced translocation, 46,XY, t(14;21)(q11.2;q11.2), as does the patient's paternal grandmother. Uniparental disomy studies using seven informative polymorphic nucleotide repeat markers from 14q and 21q confirmed biparental inheritance of the number 14 and 21 chromosomes for each brother, and indicate that they and the paternal aunt, all of whom inherited the der(14), are monosomic for proximal 21q and trisomic for proximal 14q. These karyotypes arose through an adjacent-2 segregation in the father on two occasions, and from the paternal grandmother on one occasion. This family is an example of recurrent malsegregation with translocations involving the acrocentrics.

Adult↗
PubMed2005

An MCA/MR syndrome with hypocholesterolemia due to familial hypobetalipoproteinemia: report of a second patient with Nguyen syndrome.

[Nguyen et al. (2003); Am J Med Genet 121A: 109-112] reported a boy with severe hypocholesterolemia due to autosomal dominant hypobetalipoproteinemia (ADBHL) associated with severe growth retardation, mental deficiency, epicanthal folds, a short nose with low nasal bridge and anteverted nares and bilateral partial cutaneous syndactyly of toes 2 and 3. Many of these manifestations resembled those in a mild form of Smith-Lemli-Opitz syndrome (SLOS). We report on a 13-year-old boy with ADHBL, who manifested a SLOS-like phenotype, including mental retardation and a characteristic face, similar to that of a patient reported by [Nguyen et al. (2003); Am J Med Genet 121A: 109-112]. Our patient supports the hypothesis by [Nguyen et al. (2003); Am J Med Genet 121A: 109-112] that ADHBL induced cholesterol deficiency has a significant effect on morphogenesis during embryogenesis, although additional genetic or environmental factors may be required to develop an SLOS-like phenotype in individuals with ADHLB. This is a second case of Nguyen syndrome.

Abnormalities, Multiple↗
PubMed2005

A syndrome characterized by contractures and pterygia of upper body associated with umbilical hernia, short stature, and distinctive face in an Arabic family.

A large Moslem Arabic family from the North of Israel is presented in which nine individuals are affected with short stature (5th centile and below), variable pterygium of neck or short neck with limited range of motion, pterygium of elbows, short palms, and brachydactyly. Other abnormalities of the fingers include syndactyly, camptodactyly, and/or hypermobility of the small joints. The face typically appeared long and myopathic. Ptosis was present with downslanting palpebral fissures, facial movements were reduced and the midface was flat. Umbilical hernia was present together with hypoplasia of the skin in the periumbilical area. The lower body region was unaffected in this family. The family is characterized by multiple consanguineous marriages, and the pedigree is consistent with autosomal recessive inheritance. The phenotype seems to be distinct from other multiple pterygium syndromes because the lower limbs are spared, and the umbilical hernia with hypoplastic skin has not been described previously.

Adolescent↗
PubMed2006

Orofaciodigital syndrome with cerebral dysgenesis.

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.

Abnormalities, Multiple↗
PubMed2006

A new syndrome of microtia with mixed type hearing loss, renal agenesis, and multiple skeletal anomalies.

We report on a 17-year-old man who presented with unreported combination of right sided microtia and preauricular skin tag with conductive hearing loss, unilateral renal agenesis, partial syndactyly of forth and fifth metacarpals, multiple tarsal coalitions, absent toe, and hypoplastic tibia and fibula. Radiological and clinical findings did not match with the previously described syndromes with the type of anomalies seen in the case. We propose that this represents a new syndrome.

Abnormalities, Multiple↗
PubMed2006

Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients.

Split hand foot malformation (SHFM) also known as central ray deficiency, ectrodactyly and cleft hand/foot, is one of the most complex of limb malformations. SHFM can occur as an isolated malformation or in association with other malformations, as in the ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and other autosomal dominant conditions with long bone involvement, all showing variable expressivity and reduced penetrance. The deficiency in SHFM patients can also be accompanied by other distal limb anomalies including polydactyly and/or syndactyly. This variability causes the phenotypic classification of SHFM to be far from straightforward and genetic heterogeneity, with at least five loci identified to date, further complicates management of affected patients and their families. Although genotypic-phenotypic correlations have been proposed at the molecular level for SHFM4 patients who have mutations in the P63 gene, phenotypic correlations at the chromosomal level have not been thoroughly documented. Using descriptive epidemiology, Chi square and discriminant function analyses, our laboratory has identified phenotypic patterns associated with the mapped genetic SHFM loci. These findings can assist in classification, provide insight into responsible developmental genes and assist in directing mapping efforts and targeted genetic testing, resulting in more accurate information for family members in the clinical setting. Comparison with relevant animal models is discussed.

Abnormalities, Multiple↗
PubMed2006

Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation.

Split-hand/foot malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.

Abnormalities, Multiple↗
PubMed2006

Familial occurrence of multiple pterygium syndrome: expression in a heterozygote of the recessive form or variability of the dominant form?

We report on a case with apparently familial multiple pterygium syndrome (MPS). The proposita was a 3-year-old girl with classical symptoms of MPS. A careful clinical examination of the father disclosed the presence of few minor signs of the syndrome, including difficulty in opening the mouth widely, scoliosis, pectus excavatum, hands with slight cutaneous syndactyly, and bilateral single palmar creases. The radiograph of the hands disclosed malformed carpal bones and an altered metacarpal-phalangeal pattern. The father shows limited symptoms, which has been reported before in the autosomal dominant form of MPS. However, it is also possible that he is showing a heterozygous state of the autosomal recessive form of MPS. In conclusion, we emphasize the importance of examining accurately the parents of a child who has classical MPS phenotype, even those with normal stature and an absence of facial anomalies.

Abnormalities, Multiple↗
PubMed2006

Further phenotypic and genetic variation in ADULT syndrome.

ADULT (Acro-dermato-ungual-lacrimal-tooth) syndrome is characterized by ectrodactyly, syndactyly, fingernail and toenail dysplasia, hypoplasia of the breast and nipple, excessive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and/or early loss of permanent teeth. It is a rare autosomal dominant disorder which has been linked to mutation in the p63 gene. The p63 gene has been described in five overlapping limb malformation syndromes including the EEC syndrome (ectodermal ectrodactyly clefting). We report on the first case of ADULT syndrome of a mother and daughter with a new mutation R227Q in exon 6 of the p63 gene. This has not been previously associated with ADULT syndrome but only seen in EEC. In addition to the previously reported features of ADULT syndrome this report also describes some additional findings including hyperextensibility at the distal interphalageal joints, bilateral thumb duplication, bifid toenails, symptoms of urinary retention, vesicoureteric reflux, prominent ears, conductive hearing loss, and an overgrowth of a patch of hair in the midline of the neck. This report expands the knowledge of genotype-phenotype data on the p63 gene and suggests there may be a considerable overlap between the EEC syndrome and the ADULT syndrome.

Abnormalities, Multiple↗
PubMed2003

Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: postulated involvement of the sonic hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia.

BACKGROUND: RSH/Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2-3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated. METHODS: We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes. RESULTS: Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis. CONCLUSIONS: The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD +/- common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations.

Consanguinity↗
PubMed2003

Multiple congenital anomalies associated with in utero exposure of phenytoin: possible hypoxic ischemic mechanism?

BACKGROUND: The characteristics of the phenotype of the malformed phenytoin-exposed infant can help to clarify the mechanism of the drug's teratogenesis. One postulated mechanism is vascular disruption. CASE: An infant who was exposed to phenytoin as monotherapy throughout pregnancy was born with the following abnormalities: midface hypoplasia, digit hypoplasia with syndactyly in the hands and feet, meningomyelocele, talipes equinovarus, and a long skin pedicle on the back. The mother was also exposed to cigarette smoking and alcohol during the pregnancy. CONCLUSIONS: The malformations of the hands and feet, and the talipes deformity are potential effects of vascular disruption, a postulated fetal effect of both phenytoin and cigarette smoking. The mechanism of the teratogenicity of phenytoin may have included episodes of bradyarrhythmia in the fetus; however, no such episodes were documented.

Abnormalities, Drug-Induced↗
PubMed2004

Reduced birth defects caused by maternal immune stimulation in methylnitrosourea-exposed mice: association with placental improvement.

BACKGROUND: Methylnitrosourea (MNU) is a potent carcinogen and teratogen that is associated with central nervous system, craniofacial, skeletal, ocular, and appendicular birth defects following transplacental exposure at critical time points during development, and preliminary studies have suggested that nonspecific maternal immunostimulation may offer protection against development of these birth defects. METHODS: Our study examined morphologic alterations in fetal limb and digital development and placental integrity following maternal exposure to MNU on GD 9 in CD-1 mice, and characterized the improvement in placental integrity and abrogation of fetal defects following maternal immune stimulation with interferon-gamma (IFN-gamma) on GD 7. RESULTS: Fetal limbs were significantly shortened (p < 0.0001) and incidence of limb and digital defects (syndactyly, polydactyly, oligodactyly, clubbing, and webbing) was dramatically increased following mid-gestational maternal MNU exposure. Maternal immune stimulation with IFN-gamma on GD 7 lessened incidence of fetal limb shortening and maldevelopment on GD 12 and 14. Further, disruption of placental spongiotrophoblast integrity, increased cell death in placental trophoblasts with increased intercellular spaces in the spongiotrophoblast layer and minimal inflammation, and increased loss of fetal labyrinthine endothelial cells from MNU-exposed dams suggested that MNU-induced placental breakdown may contribute to fetal limb and digital maldevelopment. MNU + IFN-gamma was associated with diminished cell death within all layers of the placenta, especially in the labyrinthine layer. CONCLUSIONS: These data verify improved distal limb development in MNU-exposed mice as a result of maternal IFN-gamma administration, and suggest a link between placental integrity and proper fetal development.

Abnormalities, Drug-Induced↗
PubMed2005

A novel insertion in the FGFR2 gene in a patient with Crouzon phenotype and sacrococcygeal tail.

BACKGROUND: Mutations in the FGFR2 gene are present in several syndromes with craniosynostosis, such as Pfeiffer's, Apert's, and Crouzon's. CASE: We report a case of craniosynostosis (Crouzon phenotype) with tracheal anomalies and a sacrococcygeal tail. In addition, the patient shows dolichoplagiocephaly, prominent occiput, proptosis, mild facial asymmetry, strabismus, small umbilical hernia, and syndactyly of the second and third toes. CONCLUSIONS: Molecular analysis of the FGFR2 gene in this patient revealed a 12-bp insertion (GAGGAGACCTAG) at nucleotide 824. This is an in-frame mutation that adds four amino acid residues to the immunoglobulin IIIa (IgIIIa) domain of the putative protein. This is the first report of an in-frame insertion in exon 8 of FGFR2 in a child with Crouzon's syndrome, tracheal anomalies, and a tail.

Base Sequence↗
PubMed2005

Smith-Lemli-Opitz syndrome in trisomy 13: how does the mix work?

BACKGROUND: Trisomy 13 and Smith-Lemli-Opitz syndrome (SLOS) are both well-recognized multiple congenital anomaly/mental retardation syndromes. CASE: In this report we describe a male newborn with trisomy 13 who also has features of SLOS, such as 2/3 toe syndactyly and a shawl-like scrotum. Biochemical analysis was consistent with SLOS, and limited molecular analysis revealed 1 mutation in the DHCR7 gene. CONCLUSIONS: The challenges in establishing the diagnosis of SLOS in this patient are presented and the unique coexistence of the 2 major malformation syndromes is discussed. Given the overlapping phenotype of the 2 syndromes, our report should encourage further research on cholesterol biosynthesis in patients with trisomy 13.

Abnormalities, Multiple↗