Digital Anomalies Research Articles

Delineation of a 1.65 Mb critical region for hemihyperplasia and digital anomalies on Xq25

Duplications involving portions of the long arm of the X-chromosome can be associated with mental retardation, short stature, microcephaly, panhypopituitarism, and a wide range of physical findings. Less common are duplications in distal Xq associated with hemihyperplasia and digital anomalies. We report on a 4-year-old female with hemihyperplasia, syndactyly of fingers and toes, bilateral 5th finger clinodactyly, short stature, developmental delay, and microcephaly associated with an 11.2 Mb duplication of Xq25-Xq27.1. The boundaries of this duplication were mapped using high resolution array comparative genome hybridization and follow-up studies revealed that the same duplication was carried by the patient's mother who has short stature and cognitive disabilities. Using the duplication boundaries from this case, and data from previously published reports, we have delineated a 1.65 Mb critical region for hemihyperplasia and digital anomalies on chromosome Xq25. Based on these findings physicians should consider obtaining array comparative genome hybridization studies on individuals with hemihyperplasia especially when accompanied by digital findings since identification of an Xq25 duplication can dramatically change recurrence risk estimations and may also provide insight into the possible comorbidities.

Mayer-Rokintansky-Kuster-Hauser Syndrome Associated with Atrial Septal Defect, Partial Anomalous Pulmonary Venous Connection and Unilateral Kidney – An Unusual Triad of Anomalies

Mayer Rokintansky-Kuster-Hauser syndrome is characterized by the congenital absence of the vagina with a variety of Müllerian duct anomalies. Because of normal sexual development, the syndrome usually remains undetected until primary amenorrhea and/or difficulty in attempting sexual intercourse result in the diagnosis. MRKHS frequently is associated with anomalies of the urinary tract (unilateral agenesis, or ectopia of one or both kidneys, horse-shoe kidney), cervico-thoracic region (asymmetric, fused or wedged vertebrae, scoliosis and Klippel-Feil anomaly), congenital cardiac defects, hearing defects, and digital anomalies of varying severity. Congenital heart diseases in the form of atrial septal defect, Holt-Oram Syndrome with or without aorticopulmonary window, pulmonary stenosis etc in association with MRKHS have been described in the literature. We present a case of MRKHS with unilateral agenesis of the kidney and atrial septal defect with partial anomalous pulmonary venous connection. This combination of anomalies has not been reported in the literature so far. The various presentations and the pathogenesis of the condition are discussed.

High resolution magnetic anomaly map of Tenerife, Canary Islands

This study presents magnetic anomaly data from a new high-resolution, low-altitude helicopter-borne magnetic survey recently collected on and offshore Tenerife in the Canary Archipelago. The Italian Istituto Nazionale di Geofisica e Vulcanologia (INGV) in collaboration with the Museo Nacional de Ciencias Naturales of the CSIC of Spain conducted the survey in 2006. The data for Tenerife and surrounding marine areas were processed into digital total intensity magnetic anomalies for geomagnetic epoch 2006.4. Relative to previously available higher altitude magnetic survey data, the new survey mapped higher resolution anomalies with significantly improved spatial details, especially over the Las Canadas caldera and Teide-Pico Viejo complex in the central part of the island. A good correlation is evident between known structural geology and the magnetic anomalies, where the new shorter wavelength anomalies facilitate more detailed and comprehensive geologic interpretations.

“At fingers’ ends”: risk factors and perinatal outcome of pregnancies complicated by digital malformations

To identify the incidence, risk factors, and perinatal outcome of newborns with congenital finger or toe (digital) anomalies. A retrospective study including all neonates born at a tertiary medical center during 2001-2006 with congenital digital anomalies was conducted. The comparison group consisted of newborns without such anomalies born during the same period. Of 115,876 newborns delivered during the study period, 360 (31 per 10,000) were diagnosed with digital anomalies. Polydactyly was the most common diagnosis (n=263; 73% of digital anomalies). Associated anomalies in these patients were congenital heart malformations (n=93; 25.8% of the newborns with congenital digital anomalies), central nervous system anomalies (n=17; 4.7%), and musculoskeletal anomalies (n=13; 3.6%). Newborns with congenital digital anomalies were more likely to be males (62.2 vs. 37.8%; P<0.001), and of a Bedouin Arab descent compared to Jewish ethnicity (61.4 vs. 38.6%; P=0.004). Significantly higher rates of severe pre-eclampsia, recurrent abortions, transverse lie, and low birth-weight (<2,500g) infants were found among newborns with digital anomalies. The incidence of digital anomalies can vary according to the population characteristics. It may be associated with other skeletal and non-skeletal malformations as well as with certain adverse obstetrical and perinatal outcomes. If a fetal digit anomaly is suspected, a detailed assessment of fetal anatomy is mandatory to exclude other malformations.

Presentation of lacrimo-auriculo-dento-digital (LADD) syndrome in a young female patient

Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM #149730) is an autosomal-dominant congenital disorder that can be caused by heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 (FGFR2) and 3 (FGFR3), and has been found in association with a mutation in the FGF10 gene, which encodes an Fgfr ligand. Clinical signs vary, but the condition is characterised by involvement of the lacrimal and salivary systems, cup-shaped ears, hearing loss and dental abnormalities. Additional features may include involvement of the hands and feet with other body systems particularly the kidneys. Previous literature on the subject has been reviewed and this case is the first presentation of LADD syndrome in the Republic of Ireland, as a sporadic case in a 12-year-old girl who exhibited a range of dental and digital anomalies. Her general medical practitioner managed her medical care whilst her oral care necessitated a multidisciplinary approach involving restorative and orthodontic elements. The initial restorative phase of treatment has successfully improved the appearance of the patient's anterior teeth using direct resin composite build-ups.

Gingival overgrowth, congenital generalized hypertrichosis, mental retardation and epilepsy: case report and overview

We report on a patient with congenital generalized hypertrichosis, mental retardation, tonic-clonic seizures with onset during the first year of life and gingival overgrowth, unrelated to antiepileptic treatment. This phenotype represents a unique combination of features, bridging the variable association of gingival overgrowth, generalized hypertrichosis, mental retardation or epilepsy. This may occur in combination with nail and/or digital anomalies, as in Zimmermann-Laband syndrome, and the broader phenotypes of the Anavi, Göhlich-Ratmann and Ramon syndromes. On the basis of the clinical overlap between our patient and these disorders inherited either as autosomal dominant or recessive traits and unknown molecular defects, a recurrence risk of one in four was considered appropriate.

A novelGJA1 missense mutation in a Polish child with oculodentodigital dysplasia

Oculodentodigital dysplasia (ODDD) (OMIM #164200) is a rare congenital, autosomal dominant disorder comprising craniofacial, ocular, dental, and digital anomalies. The syndrome is caused by GJA1 mutations. The clinical phenotype of ODDD involves a characteristic dysmorphic facies, ocular findings (microphthalmia, microcornea, glaucoma), syndactyly type III of the hands, phalangeal abnormalities, diffuse skeletal dysplasia, enamel dysplasia, and hypotrichosis. In a Polish child with the clinical symptoms typical of ODDD, we demonstrated a novel missense mutation c.C31A resulting in p.L11F substitution. Our report provides evidence on the importance of this highly conserved amino acid residue for the proper functioning of GJA1 protein.

Developmental anomalies with features of disorganization (Ds) and amniotic band sequence (ABS): A report of four cases

Disorganization (Ds) is a mouse mutant in which heterozygotes manifest defects in various organ systems including cranioschisis, hamartomas, limb abnormalities, body wall defects, eye defects, and craniopharyngeal defects. We report four patients with developmental anomalies that are seen in amniotic band sequence (ABS) with additional anomalies that could not be explained by amniotic bands alone. The anomalies seen in our patients included facial malformation and clefting, brain anomalies (encephalocele, agenesis of the corpus callosum, holoprosencephaly), eye anomalies (anophthalmia, microphthalmia, and microcornea), and extremity and digit anomalies (talipes equinovarus, absent/hypoplastic phalanges, amputation of an extremity, syndactyly, polydactyly, and anomalous attachment of an extremity). Other systems involved include genitourinary anomalies (hydronephrosis and abnormal testes, epidydimis and seminal vesicles), and skin appendages similar to those seen in Ds mice. Presence of amniotic bands in addition to malformations not attributed to amniotic bands, were seen in three of four patients. The four patients in this report have involvement of at least four organ systems including the skin appendages that have been reported in the Ds mouse and have clinical findings that overlap the spectrum of Ds and ABS.

Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: Phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?

A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Molecular characterization of co‐occurring Duchenne muscular dystrophy and X‐linked oculo‐facio‐cardio‐dental syndrome in a girl

Duchenne muscular dystrophy is an X-linked condition at the severe end of the spectrum of dystrophinopathies. Females with dystrophin mutations are at risk for cardiomyopathy, but are usually asymptomatic during childhood. However, some girls can exhibit features of Duchenne muscular dystrophy because of skewed X-inactivation, aneuploidy, or chromosomal rearrangement. Oculo-facio-cardio-dental syndrome is a rare X-linked disorder, lethal in males, that comprises microphthalmia, congenital cataracts, congenital heart defect, canine radiculomegaly, and digital anomalies. We report on a 7-year-old girl who was referred for muscular hypotonia, with clinical features of Duchenne muscular dystrophy, including elevated serum creatine phosphokinase, pseudohypertrophy of calf muscles, and muscle weakness, which became evident at 3 years of age. In addition, she had multiple congenital anomalies including atrial septal defect, cataracts, dental and digital anomalies, a constellation that suggested the diagnosis of oculo-facio-cardio-dental syndrome, a condition caused by mutations in BCOR. Immunohistochemistry and Western blot analysis of muscle, and mutation analysis of DMD showed a maternally inherited deletion of exons 30-43, confirming the diagnosis of Duchenne muscular dystrophy. Studies of lymphocytes showed essentially complete skewing of X-inactivation. Mutation analysis of BCOR revealed a de novo frameshift mutation (c.1005delC). Thus, we report for the first time on an individual with the co-occurrence of Duchenne muscular dystrophy and oculo-facio-cardio-dental syndrome.

Loss of connexin43-mediated gap junctional coupling in the mesenchyme of limb buds leads to altered expression of morphogens in mice

Mutations in the GJA1 gene coding for connexin43 (Cx43) cause oculodentodigital dysplasia (ODDD), a pleiotropic human disorder with characteristic morphologic anomalies of face, teeth, bones and digits. Interdigital webbings, also called syndactylies, are a characteristic phenotype of this disease showing high intra- and interfamilial penetrance. Therefore, we decided to study the molecular basis of syndactylies caused by Cx43 mutations. In order to reveal the impact of Cx43-mediated gap junctional coupling, we used mice expressing the human point mutation Cx43G138R and, in addition, 'knock-out' mice lacking Cx43. Both conditional mouse models developed syndactylies as a consequence of disturbed interdigital apoptosis, which we show to be due to reduced expression of two key morphogens: sonic hedgehog (Shh) and bone morphogenic protein 2 (Bmp2). Diminished levels of Bmp2 and subsequent up-regulation of fibroblast growth factors (Fgfs) lead to an insufficient induction of interdigital apoptosis. Interestingly, the reduction of Shh expression in Cx43 mutants begins on embryonic day 10.5 indicating a disturbance of the Fgf/Shh regulatory feedback loop, and confirming the recently published observation that gap junctions can relay Fgf signals to neighboring cells. Thus, Cx43-mediated gap junctional coupling in the mesenchyme of limb buds after ED11 is essential to maintain Shh expression, which regulates the downstream signaling of Bmp2. Besides diminished interdigital apoptosis, the decreased expression of Bmp2 in Cx43 mutants may also be involved in other morphological alterations in patients suffering from ODDD.

Carpal Tunnel Syndrome Due to Fibrolipomatous Hamartoma of the Median Nerve in Klippel-Trénaunay Syndrome

Klippel-Trenaunay syndrome is a rare congenital disorder that is characterized by the triad of cutaneous capillary malformation, varicose veins, and hypertrophy of bone and soft tissue1. It is associated with numerous digital anomalies, including macrodactyly, which is observed in 24% of patients2. Carpal tunnel syndrome is rarely associated with Klippel-Trenaunay syndrome, and only a few cases have been reported3-7. The proposed pathogenesis of carpal tunnel syndrome in a patient with Klippel-Trenaunay syndrome is either lymphatic obstruction or abnormal lymphatic proliferation, which causes an increase in pressure inside the carpal tunnel, or cavernous hemangioma surrounding the median nerve. We report a rare case of carpal tunnel syndrome due to fibrolipomatous hamartoma of the median nerve in a patient with Klippel-Trenaunay syndrome. Fibrolipomatous hamartoma is characterized by the expansion of the epineurium by fibrofatty tissue that surrounds and separates the nerve fascicles8; it usually involves the median nerve3,8-10. The pathophysiology of the structures inside the carpal tunnel was investigated in our patient, and attempts were made to compare the findings in the present case with those of idiopathic carpal tunnel syndrome. The patient was informed that data concerning the case would be submitted for publication, and he consented. A forty-six-year-old man with bilateral macrodactyly presented with pain and numbness in the thumb and the index and long fingers of the right (dominant) hand. He had been diagnosed with Klippel-Trenaunay syndrome at birth. The family history was unremarkable for congenital abnormalities. At twelve years of age, the patient began to experience numbness in the thumb and the index and long fingers of the right hand. At fifteen years of age, he noticed a soft mass in the right palm, although the symptoms remained unchanged. At the age …

The trouble with flippers: a report on the prevalence of digital anomalies in Cetacea

The forelimbs of cetaceans (whales, dolphins, and porpoises) are unique among mammals as the digits exhibit hyperphalangy, and the entire limb is encased in a soft tissue flipper that functions to generate lift. The typical morphology of cetacean digits has been well documented by detailed anatomical studies. This study however furthers our understanding of cetacean forelimb anatomy by conducting a taxonomically broad survey of cetacean digital anomalies. Forelimb radiographs from museum collections provided the basis upon which we calculated the prevalence and documented the morphology of cetacean digital abnormalities. Results indicated that 11% (n = 255) of toothed whales displayed some type of aberrant ossification: the majority of these cases displayed a fusion of elements within a single digital ray, whereas cases exhibiting branched digits were rare. A small sample of baleen whale radiographs (n = 6) contained the only documented case of baleen whale polydactyly in a specimen of the gray whale (Eschrichtius). Furthermore, some Balaenoptera specimens displayed ossified elements within the interdigital spaces that lacked attachment to the adjacent digits and carpus. In addition, we speculated on the role that several genes may have played in creating cetacean digital anomalies. © 2009 The Linnean Society of London, Zoological Journal of the Linnean Society, 2009, 155, 722‐735.

Lesser Forms of Cleft Lip Associated With the Branchio-Oculo-Facial Syndrome

Lesser forms of incomplete cleft lip (CL) have been called microform, occult, forme fruste, and congenitally healed. The association of a minimal bilateral CL in branchio-oculo-facial syndrome (BOFS) is well described and commonly referred to as a "pseudocleft." We conducted a systematic analysis of CL types in BOFS, including a retrospective cross-sectional chart and photographic review with variable longitudinal follow-up of our patients and those described in the literature. We compared data on the type of CL and palate (CL/P) and craniofacial and extracranial anomalies in patients with BOFS and classified the lesser forms CL as either minor-form, microform, or mini-microform as defined by the extent of disruption at the vermilion-cutaneous junction. The study comprised 62 patients with BOFS (1 new and 61 in literature, 4 treated by J.B.M). Forty-four patients (71%) had CL only; 16 (26%) had CL/P; and 2 patients had neither CL nor isolated CP. Thirty-five patients with CL had adequate information for analysis (defined as either seen by J.B.M., having a published photograph, or having a detailed description). The most common type was bilateral symmetrical, lesser form CL (n = 20): minor-form (n = 2), microform (n = 6), or mini-microform (n = 12). Among 17 asymmetrical forms, the left side was more severely affected side than the right (12 vs 5). Of 9 patients with CL/P and adequate clinical description, 4 were bilaterally symmetrically complete. Other anomalies, in addition to the familiar cardinal features of BOFS, included facial nerve weakness (n = 6), chin dimple or cleft of the lower lip (n = 4), upper labial pits (n = 6), minor digital anomalies (n = 12), renal anomalies (n = 14), and ectopic thymus (n = 18). This analysis reaffirms the high frequency of CL or CL/P in BOFS and the rarity of isolated cleft palate and underscores that the term "pseudocleft" lip is incorrect. The more precise lesser form designations used in this study may prove useful for future clinical studies because the causative gene, TFAP2A, is known. Lesser forms of CL may be the most subtle expression of BOFS and assist in identifying patients. Unlike major forms of CL/P, either, syndromic or non syndromic, lesser forms suggest that the developmental insult occurs later in labial formation when fusion of the medial nasal process and maxillary process is nearly complete. The deficient vermilion-mucosa and hypoplastic orbicularis oris may be the result of incomplete or deficient mesodermal penetration of the ectodermal envelope. Another possible pathogenic explanation is that failure of labial closure occurs earlier than in a major cleft when the primitive cells of ectoderm and mesoderm retain the capacity to "heal" the defect.

Phenotypical manifestations of partial trisomy 9 and monosomy 4 in two siblings

In this case report, we describe two siblings with a previously unreported partial monosomy 4q and partial trisomy 9q. The sibling karyotypes were determined to be 46,XX,der(4)t(4;9)(q33;q33)pat and 46,XY,der(4)t(4;9)-(q33;q33)pat. The siblings share several common pathological features, including VSD, PDA, low-set ears and digit anomalies as well as features consistent with Pierre-Robin syndrome and hydrocephalus. We review previously reported phenotypes associated with monosomy 4q and partial trisomy 9q and discuss potential mechanisms for these morphological insults with particular emphasis on neuropathology.

Bilateral Anterior Hip Dislocation in a Child With Aarskog Syndrome

Both Aarskog syndrome and atraumatic anterior hip dislocation are rare entities. Aarskog syndrome is an X-linked recessive disorder with facial, digital, and genital anomalies and is associated with varying degrees of ligamentous laxity. This is believed to be the only known reported case of bilateral anterior voluntary dislocating hips in an ambulatory child and the only reported case of hip dislocation in a child with Aarskog syndrome. Staged bilateral varus derotational femoral osteotomies and Dega osteotomies were successfully performed. Hardware was removed 1 year after the second operation. The patient has been asymptomatic at 2 years' follow-up. This article calls attention to the features of Aarskog syndrome and potential orthopaedic concerns.

Genotype-phenotype correlations in MYCN-related Feingold syndrome

Feingold syndrome (FS) is the most frequent cause of familial syndromic gastrointestinal atresia and follows autosomal dominant inheritance. FS is caused by germline mutations in or deletions of the MYCN gene. Previously, 12 different heterozygous MYCN mutations and two deletions containing multiple genes including MYCN were described. All these mutations result in haploinsufficiency of both the canonical MYCN protein and the shorter isoform, DeltaMYCN. We report 11 novel mutations including seven mutations in exon 2 that result in a premature termination codon (PTC) in the long MYCN transcript. Moreover, we have identified a PTC in exon 1 that only affects the DeltaMYCN isoform, without a phenotypic effect. This suggests that mutations in only DeltaMYCN do not contribute to the FS. Additionally, we found three novel deletions encompassing MYCN. Together with our previous report we now have a total of four missense mutations in the DNA binding domain, 19 PTCs of which six render the transcript subject to nonsense-mediated decay (NMD), and five larger deletions in a total of 77 patients. We have reviewed the clinical features of these patients, and found that digital anomalies, e.g., brachymesophalangy and toe syndactyly, are the most consistent features, present in 100% and 97% of the patients, respectively. Small head circumference was present in 89% of the cases. Gastrointestinal atresia remains the most important major congenital anomaly (55%), but cardiac and renal anomalies are also frequent. We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.

Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome

Klippel-Feil syndrome (KFS) is a congenital disorder of spinal segmentation distinguished by the bony fusion of anterior/cervical vertebrae. Scoliosis, mirror movements, otolaryngological, kidney, ocular, cranial, limb, and/or digit anomalies are often associated. Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with carpal, tarsal, and vertebral fusions. GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc. GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, diversity, and variability of KFS.

Intellectual Disability

A “microdeletion” on chromosome 15 is associated with a new syndrome characterized by intellectual disability, epilepsy, and facial and digital anomalies, according to an international team of scientists (Sharp AJ. Nat Genet. 10.1038/ng.93 [published online ahead of print February 17, 2008]).

Subglossopalatal Synechia in Association with Cardiac and Digital Anomalies

A 1-day-old boy in respiratory distress had a midline soft tissue band between the floor of the mouth and the posterior edge of the hard palate. There was also a soft palatal cleft, cardiac anomalies, and a hypoplastic right fifth finger and toe. Although his airway initially improved following urgent excision of the subglossopalatal band, he continued to have episodic desaturations. A tongue-lip adhesion opened his airway, and he subsequently underwent resection of juxtaductal aortic coarctation and ligation of patent ductus arteriosus and left superior vena cava. Congenital oral synechiae are uncommon. Affected infants often require prompt intervention secondary to respiratory distress and feeding difficulty. Review of the literature indicates that midline subglossopalatal synechia with cardiac and digital anomalies may be in the oromandibular-limb hypogenesis spectrum.