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PubMed2000

[Feingold syndrome].

BACKGROUND: Feingold syndrome is a combination of hand and foot anomalies, microcephaly, tracheo-esophageal fistula, esophageal/duodenal atresia, short palpebral fissures and developmental delay. The most frequent physical findings are clinodactyly of the second and fifth fingers with absent or hypoplastic middle phalanges, and syndactyly of the toes. Inheritance is autosomal dominant (MIM number 164280) with full penetrance concerning hand anomalies, variable expressivity and great intrafamilial variability. CASE REPORT: We report the case of an African boy with duodenal atresia, microcephaly, brachymesophalangy of the second and fifth fingers, unilateral thumb hypoplasia, bilateral syndactyly of toes 2-3 and amesophalangy of the toes. Karyotype was normal. No other member of the family was affected. A fresh mutation is possible. CONCLUSION: Brachymesophalangy affecting mainly the second and fifth fingers and amesophalangy of the lateral toes are cardinal clinical findings in Feingold syndrome. These clinical findings define the syndrome of brachydactyly A4-Temtamy type (MIM 112800), suggesting that brachydactyly A4 would be a partially expressed Feingold syndrome. The incidence of esophageal/duodenal atresia is 29%, including all the known cases. All karyotypes of reported patients were normal.

Abnormalities, Multiple↗
PubMed1997

Mutations of the TWIST gene in the Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism including ptosis, facial asymmetry and prominent ear crura. ACS III has been mapped to chromosome 7p21-22. Of interest, TWIST, the human counterpart of the murine Twist gene, has been localized on chromosome 7p21 as well. The Twist gene product is a transcription factor containing a basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogenesis in mice. The co-localisation of ACS III and TWIST prompted us to screen ACS III patients for TWIST gene mutations especially as mice heterozygous for Twist null mutations displayed skull defects and duplication of hind leg digits. Here, we report 21-bp insertions and nonsense mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and describe impairment of head mesenchyme induction by TWIST as a novel pathophysiological mechanism in human craniosynostoses.

Acrocephalosyndactylia↗
PubMed1999

Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome.

Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome.

Acrocephalosyndactylia↗
PubMedDate not supplied

Radiographic analysis of transverse plane digital alignment after surgical repair of the second metatarsophalangeal joint.

We undertook a retrospective cohort study of 51 feet in 49 patients with surgically managed second metatarsophalangeal joint instability, including repair of the crossover second toe deformity. The fundamental intervention consisted of proximal interphalangeal joint arthrodesis combined with second metatarsophalangeal joint relocation and Kirschner-wire transfixation, and this was performed alone or in combination with one of the following additional surgical maneuvers: flexor tendon transfer or flexor set release, flexor plate repair, placement of a plantar-lateral retention suture, extensor tendon transfer, metatarsophalangeal arthroplasty, metatarsal osteotomy, or second-to-third syndactyly. The outcome of interest was the presence of a transverse plane second metatarsophalangeal joint angle of 0 degrees to 15 degrees measured on the late postoperative follow-up radiograph. Overall, the median angular correction for all second metatarsophalangeal joint interventions was 8 degrees , and second-to-third syndactyly yielded the most long-term correction followed by, in descending order of the amount of angular correction, use of the fundamental intervention in combination with metatarsophalangeal joint arthroplasty, placement of a plantar-lateral anchor suture in the flexor plate, metatarsal osteotomy, flexor tendon transfer, flexor plate repair, extensor tendon transfer, and the fundamental intervention as a solitary procedure. A sensitivity analysis indicated that our results were resistant to the influence that an unmeasured variable would impart on the data. The results of this investigation should aid surgeons treating patients with unstable second metatarsophalangeal joints, and can be used in the development of future clinical trials and observational studies that focus on the management of this common deformity.

Adult↗
PubMed1998

Surgical management of hands in children with recessive dystrophic epidermolysis bullosa: use of allogeneic composite cultured skin grafts.

Recessive dystrophic epidermolysis bullosa (RDEB) is characterised by progressive childhood hand syndactyly and flexion contractures, which can be managed surgically but require split thickness autografts to facilitate satisfactory postoperative healing. We report on the partial substitution, for autografts, of improved composite cultured skin (CCS) allografts. The structure and preparation of these CCSs is outlined and their application in the course of 16 operations performed on 7 RDEB children with syndactyly and flexor contractures of fingers is described. Hand contractures were released and web spaces were covered with local flaps and split thickness autografts, while adjacent sides of the digits and other areas, as well as donor sites were generally grafted with CCS. Morphologic and functional results with CCS were judged to be good to excellent, the average time to recurrence was increased approximately 2-fold and smaller autografts needed to be used. In addition, healed CCS-treated donor sites could provide superior donor sites for further surgery.

Adolescent↗
PubMed2002

Acrocephalosyndactyly -- the coalesced hand.

Described nearly a century ago, Apert's Syndrome (A.S.) is a rare disorder affecting 1/80,000 children, the mode of inheritance is autosomal dominant or sporadic. Apart from the more obvious skull malformations, extensive and complex hand deformities create several problems for the child's interaction with its environment, preventing normal intellectual development and generating psychological problems as severe as those caused by the craniofacial abnormalities. The deformities seen here are some of the most complex of all congenital hand malformations. Between January 1987 and January 1999, 71 children presenting with hand syndactyly were treated at the Hospital de Dona Estefania (H.D.E.), a total of 177 syndactylies. Of those, 51 had no associated illnesses, 14 had other conditions and six had A.S. All six cases were sporadic; one child had a cleft palate and another suffered from epilepsy. The timing at which the various surgeries were performed was diverse, however, there has been a recent trend towards earlier interventions in order to obtain a functional hand before the age of two. Aesthetic results vary a lot depending on the complexity of the lesions and we sometimes accept a three or four-digit, but functional hand. We achieved hands with a function of 40 to 65 % in all our patients before school age. Due to A.S.' rarity, an effective use of resources and good results can only be obtained in a specialised centre with a multidisciplinary team.

Acrocephalosyndactylia↗
PubMed2005

Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.

Action Potentials↗
PubMed1999

EEM syndrome: report of a family and results of a ten-year follow-up.

We report on a Brazilian kindred in which two sibs presented with the complete form of EEM (ectodermal dysplasia, ectrodactyly, and macular dystrophy) syndrome with hypotrichosis, dental anomalies, syndactyly, and retinal changes with prominent pigmentation in the posterior pole of the retina. In this family, we also observed another sib with syndactyly, as well as a first cousin with ectrodactyly. A 10-year follow-up demonstrated gradually decreasing visual acuity and progression of retinal degenerative anomalies.

Adult↗
PubMed1999

De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.

Apert syndrome, one of five craniosynostosis syndromes caused by allelic mutations of fibroblast growth-factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and feet. We have analyzed 260 unrelated patients, all but 2 of whom have missense mutations in exon 7, which affect a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. FGFR2 mutations in the remaining two patients are distinct in position and nature. Surprisingly, each patient harbors an Alu-element insertion of approximately 360 bp, in one case just upstream of exon 9 and in the other case within exon 9 itself. The insertions are likely to be pathological, because they have arisen de novo; in both cases this occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth-factor receptor [KGFR] and bacterially expressed kinase, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Splicing of exon 9 was examined in RNA extracted from fibroblasts and keratinocytes from one patient with an Alu insertion and two patients with Pfeiffer syndrome who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome.

Acrocephalosyndactylia↗
PubMed1997

Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.

Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.

Adult↗
PubMed2003

Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling.

Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis. Recently, it has been demonstrated that cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs. To provide insight in the functions of cholesterol during limb development and in the potential role of Hedgehog signaling in the genesis of limb defects, we developed an in vivo rat model of cholesterol deficiency. We show here that treatment with Triparanol, a distal inhibitor of cholesterol biosynthesis, induced patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, thus reproducing limb anomalies frequently observed in humans. Using in situ hybridization, we show that these malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. Our study thus unravels the molecular mechanisms underlying the genesis of limb defects associated with cholesterol deficiency in rodents, and most probably in humans.

Animals↗
PubMed2001

Differential expression of fibroblast growth factor receptors in human digital development suggests common pathogenesis in complex acrosyndactyly and craniosynostosis.

The Apert hand is characterized by metaphyseal fusions of the metacarpals and distal phalanges, symphalangism, and soft-tissue syndactyly. More subtle skeletal anomalies of the limb characterize Pfeiffer and Crouzon syndromes. Different mutations in the fibroblast growth factor receptor 2 (FGFR2) gene cause these syndromes, and offer the opportunity to relate genotype to phenotype. The expression of FGFR1 and of the Bek and KGFR isoforms of FGFR2 has, therefore, been studied in human hand development at 12 weeks by in situ hybridization. FGFRs are differentially expressed in the mesenchyme and skeletal elements during endochondral ossification of the developing human hand. KGFR expression characterizes the metaphyseal periosteum and interphalangeal joints. FGFR1 is preferentially expressed in the diaphyses, whereas FGFR2-Bek expression characterizes metaphyseal and diaphyseal elements, and the interdigital mesenchyme. Apert metaphyseal synostosis and symphalangism reflect KGFR expression, which has independently been quantitatively related ex vivo to the severity of clinical digital presentations in these syndromes. Studies in avian development implicate FGF signaling in preventing interdigital apoptosis and maintaining the interdigital mesenchyme. Herein is proposed that in human FGFR syndromes the balance of signaling by means of KGFR and Bek in digital development determines the clinical severity of soft-tissue and bony syndactyly.

Acanthosis Nigricans↗
PubMed2005

Algorithm for treatment of apert hand.

The hand in Apert syndrome is one of the most complex examples of congenital deformity of the upper limb. The management is difficult, and mny different approaches have been published. The hands demonstrate many disturbances of soft tissue and bony structures. These include a short thumb with radial clinodactyly, complex syndactyly with a bony fusion involving the index, long and ring fingers, and symphalangism and simple syndactyly of the fourth web space. The soft tissue anomalies involve the intrinsic muscles, the extrinsic tendon insertions, and the neurovascular bundles. Correction of the appearance of the operated hand is readily apparent, but the complexity of the disorders in the bones and soft tissues explains the difficulty of the surgical management. The aim of this study is to propose a better surgical management: on the basis of the experience of our multidisciplinary team (188 procedures in 53 patients) in the light of recent publications and a better comprehension of the syndrome, we attempt to reduce the number of procedures and to select the best possible procedures for each patient. When possible, we perform a 3-step procedure (the first is bilateral, the others are unilateral) between 9 months and 2 years of age. Separation of the fingers improves function even though we must expect an inevitable stiffness in extension of the interphalangeal joints.

Acrocephalosyndactylia↗
PubMed1976

A familial syndrome of cranial, facial, oral and limb anomalies.

A family is described in which two male infants have microcephaly, abnormal ears, anti-mongoloid slant, small mouth, cleft palate, flexed overlapping fingers with syndactyly of digits three and four, syndactyly of the second to the fifth toes, and normal karyotype. This seems to be a new syndrome.

Abnormalities, Multiple↗
PubMed1976

Pfeiffer syndrome: report of a family and review of the literature.

A 5-year-old boy and his father with Pfeiffer syndrome are described. They had acrocephaly, hypertelorism, antimongoloid slant of the palpebral fissures, protrusion of the eyes, large and broad nose, small mandible, irregularly placed teeth, additional upper canine, high-arched palate, partial syndactyly of fingers and toes, brachydactyly of toes, valgus deformity of hypertrophied triangular great toes, broad phalanges of the great toes and broad first metatarsals, accessory epiphyses lateral to the interphalangeal joint of the great toes, and normal intelligence. To our knowledge, this is the first family in which the syndrome is almost totally confined to the head and feet--it spares the upper limbs except for partial skin syndactyly between the fingers--and the third family showing inheritance through three successive generations suggesting an autosomal dominant mode of inheritance. The published papers are reviewed and the clinical and x-ray signs are tabulated.

Acrocephalosyndactylia↗
PubMed1993

46,XX/69,XXX diploid-triploid mixoploidy with hypothyroidism and precocious puberty.

We report a 20 month old female patient with diploid-triploid mixoploidy (46,XX/69,XXX) syndrome with hypothyroidism and precocious puberty. The triploid cell line was only expressed in the fibroblast culture and comprised the majority (95%) of the cells. Chromosome analysis of the fetal blood sample and peripheral blood sample were normal. The patient shows typical features of full triploidy (growth and severe mental retardation, cranial and facial dysmorphism, complete syndactyly of fingers 3/4, partial syndactyly of toes 2/3) and facial but no body asymmetry. At the age of 5 months central hypothyroidism and precocious puberty were diagnosed. Thin pigmented streaks were visible on the wrists and legs of the patient at the age of 16 months. This is the first patient reported so far with 46,XX/69,XXX mixoploidy suffering from hypothyroidism and precocious puberty.

Abnormalities, Multiple↗
PubMed2001

A novel acropectoral syndrome maps to chromosome 7q36.

F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia affecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 affected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 affected and nine unaffected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH.

Abnormalities, Multiple↗
PubMed2002

Saethre-Chotzen syndrome presenting with incomplete renal Fanconi syndrome.

Here we report on a patient with findings of acrocephaly, craniosynostosis, low frontal hairline, ptosis of eyelids, deviated nasal septum, broad great toes, moderate hallux valgus, bilateral symmetrical complete soft tissue syndactyly of toes 2 and 3, and partial soft tissue syndactyly of toes 4 and 5 consistent with the diagnosis of Saethre-Chotzen syndrome. Additionally, the patient had some unusual findings as part of generalized dysfunction of the renal tubules including hypophosphatemia with renal phosphate wasting, normocalcemic hypercalciuria, hypomagnesemia with renal magnesium wasting, low-molecular-weight proteinuria, decreased serum PTH levels, osteopenia, and nephrolithiasis. In the light of these findings, the diagnosis of incomplete renal Fanconi syndrome was made. In conclusion, on the basis of the present findings, it is difficult to say whether renal tubular dysfunction are somehow connected to the Saethre-Chotzen syndrome or not. Therefore, we consider that this is probably just a coincident. However, further studies may show the connection between renal tubular dysfunction and Saethre-Chotzen syndrome.

Acrocephalosyndactylia↗