Genetic regulatory pathways of split-hand/foot malformation.

Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM. Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death. Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R. Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM. Whatever the causative genes of SHFM are, the mutations seem to lead to dysregulation of Fgf8 in AER cells of the central parts of the hands and feet and disruption of Wnt-Bmp-Fgf signaling pathways in AER.

Riga-Fede Disease Associated with Syndactyly and Oligodactyly: A rare Occurrence.

Background: Eruption of first primary tooth starts on an average at around six to seven months of age. Presence of teeth at birth or within a month after birth is considered rare. Natal teeth are those present in the oral cavity at the time of birth. These teeth can cause ulcers on the ventral surface of the tongue, lip, and the mother's breast characterizing the Riga Fede Disease. Exact aetiology of natal and neonatal teeth is still unclear. The treatment depends on its mobility of teeth as it is associated with the risk of aspiration or swallowing, whether the natal tooth is supernumerary or primary, causing any problems in breast feeding, presence of soft tissue injuries on tongue of the child or mother's breast and overall health of child. Case presentation: A fifteen day old girl reported with large ulceration on ventral surface of tongue due to sharp natal teeth present at mandibular anterior region which was also associated with feeding difficulties. Along with Riga Fede disease Syndactyly and Oligodactyly in left and right legs respectively was also observed. Extraction of the teeth has been carried out and complete healing of ulceration has been achieved within 30 days. Conclusion: The present case report describes a rare occurrence of Riga Fede disease with Syndactyly and Oligodactyly and highlights its symptomatology and therapeutic approach.

Non-syndromic bilateral ulnar aplasia with humero-radial synostosis and oligo-ectro-dactyly.

Congenital anomalies of the upper limbs are rare and etiologically heterogeneous. Herein, we report a male infant with non-syndromic bilateral Type Vb ulnar longitudinal dysplasia with radiohumeral synostosis (apparent humeral bifurcation), and bilateral oligo-ectro-syndactyly who was born following an uncomplicated pregnancy, with no maternal use of prescription or illicit medication. Array CGH (60,000 probes) and chromosomal breakage analysis (DEB) were normal. Similar appearances have been reported in children exposed to thalidomide or cocaine, but sporadic patients have also been reported without a prior history of exposure to known teratogens.

Clinical diagnostic exome evaluation for an infant with a lethal disorder: genetic diagnosis of TARP syndrome and expansion of the phenotype in a patient with a newly reported RBM10 alteration.

BACKGROUND: Diagnostic Exome Sequencing (DES) has been shown to be an effective tool for diagnosis individuals with suspected genetic conditions. CASE PRESENTATION: We report a male infant born with multiple anomalies including bilateral dysplastic kidneys, cleft palate, bilateral talipes, and bilateral absence of thumbs and first toes. Prenatal testing including chromosome analysis and microarray did not identify a cause for the multiple congenital anomalies. Postnatal diagnostic exome studies (DES) were utilized to find a molecular diagnosis for the patient. Exome sequencing of the proband, mother, and father showed a previously unreported maternally inherited RNA binding motif protein 10 (RBM10) c.1352_1353delAG (p.E451Vfs*66) alteration. Mutations in RBM10 are associated with TARP syndrome, an X-linked recessive disorder originally described with cardinal features of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava. CONCLUSION: DES established a molecular genetic diagnosis of TARP syndrome for a neonatal patient with a poor prognosis in whom traditional testing methods were uninformative and allowed for efficient diagnosis and future reproductive options for the parents. Other reported cases of TARP syndrome demonstrate significant variability in clinical phenotype. The reported features in this infant including multiple hemivertebrae, imperforate anus, aplasia of thumbs and first toes have not been reported in previous patients, thus expanding the clinical phenotype for this rare disorder.

Congenital hypoplasia of first digital ray of hands as an isolated presentation in four subjects.

Congenital hypoplasia of thumb is rare malformation which is less likely to appear as an isolated entity. Four independent subjects exhibiting various grades of underdeveloped first digital ray were recruited. The affected autopods had narrow palms, medial or valgus inclinations of index fingers and thenar weakness, while the postaxial digits were least affected. According to the classification of hypoplastic thumb by Blauth and Schneider-Sickert (1981), the phenotypes were concordant with types 3 and 4. In one of the subjects there was contralateral preaxial polydactyly. All cases were sporadic and nonsyndromic and parental consanguinity was witnessed in two individuals. Recurrent appearance of similar phenotypes may suggest genetic etiologies which should be elucidated with the help of high-throughput genetic methods.

Study of non-syndromic thumb aplasia in six independent cases.

OBJECTIVES: To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype. METHODS: The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan, and underwent detailed clinical and phenotypic examination. RESULTS: The affected arms of patients had complete absence of first digital rays, medial inclinations of second and fifth fingers, narrowing of palms, missing carpals, and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies, and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects. CONCLUSION: Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia, compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations.

Bilateral ulna hemimelia with humeroradial synostosis and oligodactyly: A case report.

Hemimelia denotes the partial or complete absence of the distal half of a limb. Ulna hemimelia, a rare congenital anomaly, involves the complete or partial absence of the ulna in the upper limb, with an incidence of 1 in 150,000. This condition has been classified into 4 types, with the rare Type 4 variant involving humeroradial synostosis. We present a unique case of bilateral complete ulna hemimelia, humeroradial synostosis, and oligodactyly, in an 11-month-old female with bilateral upper limb shortening and restricted elbow movement since birth. Clinical examination revealed bilateral upper limb shortening, medial deviation of both wrist joints, fixed extension of both elbow joints, and bilateral absence of the cubital fossa. Radiographs confirmed bilateral micromelia, absence of ulna, humeroradial synostosis, and oligodactyly. This case, exhibiting bilateral Type 4 ulna hemimelia with Class 1 humeroradial synostosis, is a complex variant, rarely reported, and the first documented in Ghana. It also highlights the importance of radiological assessment in ensuring accurate diagnosis. Long-term follow-up and potential surgical interventions are crucial for optimizing upper limb function in such cases.

Ulnar aplasia, dysplastic radius and preaxial oligodactyly: Rare longitudinal limb defect in a sporadic male child.

Ulnar hypoplasia is a rare longitudinal limb deficiency in which the ulna shows various degrees of deficiency. The condition is normally associated with radial defects, and in severe cases there is a reduction of postaxial/ulnar digits. Ulnar deficiency is an integral part of several syndromic malformations like Weyer's oligodactyly syndrome, limb/pelvis hypoplasia/aplasia syndrome, and ulnar-mammary syndrome. Here, we report an isolated unilateral ulnar deficiency in a boy who was a product of a consanguineous marriage. The subject demonstrated mesomelic shortening of the left arm with reduced zeugopod and autopod, and preaxial absence of two fingers. Additional findings in the affected limb were severe flexion contracture at the elbow joint, reduced and narrow palm, hypoplastic digits, and clinodactyly. Roentgenographic study revealed rudimentary ulna, dysplastic and posteriorly dislocated radius, crowding of carpals, and complete absence of digit rays of the thumb and index finger. Despite this anomaly, the subject could manage his daily life activities well. We present detailed clinical features and differential diagnosis of this rare limb malformation.

Foot Oligodactyly as the Main Dysplasia in Children.

Introduction Foot oligodactyly is usually associated with fibular insufficiency or cleft foot syndrome. A foot with a reduced number of rays may occasionally have an isolated dysplasia. Methods We reviewed the clinical notes and X-rays of six children with oligodactyly, having a normal development of the tibia and fibula. Clinical evaluation recorded the plantigrade or deviated foot, appropriate shoe wear, and aesthetic presentation of barefoot children. Radiological examination revealed missing or hypoplastic bones in the foot, the presence of other deformities, and leg length discrepancy (LLD) of the affected limb. Results On clinical evaluation, all children except one had a plantigrade foot with normal shoe wear; the lesion was not spotted in three of them unless informed of the presence of the dysplasia. Radiological examination in four of them revealed the absence or hypoplasia of the navicular, with a normal shape of the first metatarsal. Calcaneocuboid joints were normal in five of them; LLD was the main problem in three children. The girl with bilateral oligodactyly presented as a normal child. Conclusion Oligodactyly may present as an isolated dysplasia. LLD in these patients, which is less severe than in children with fibular or tibial insufficiency, is the main issue that requires surgical management in later life. Prenatal diagnosis of oligodactyly as an isolated dysplasia is an important feature for appropriate counseling of parents.

Meaning of Disability and Management of its Visibility: a Review of a Qualitative Inquiry on People with Oligodactyly.

In this commentary, I discuss the contribution of the target article (Sulaeman et al. 2020) and suggest further study in terms of research on psychosocial issues of people with physical disabilities. The authors of the target article qualitatively analyzed the disability-related experiences of people with oligodactyly in a rural village in Indonesia, employing the theories of stigma (Goffman 1963) and illness narrative (Kleinmann 1988). First, the authors effectively found the meanings of the participants' minor daily experiences by focusing on their physical organ abnormalities. Oligodactyly is visible and mild, rather than other disabilities such as spinal cord injury. A detailed analysis is required to clarify the effect of disability. The authors found that their bodily differences and disorders had multifaceted meanings rather than negative ones only. Another finding was that "God" was referred to as a mediator connecting diverse meanings and places revealing uncertain experiences. Additionally, I discuss that the visibility of oligodactyly depends on the context, and that visible or invisible dichotomy is not suitable for studying psychosocial issues. I argue that people with mild disabilities face the dilemma of disclosing their condition to others. My suggestion for further study is to examine the development of disability meaning from a long-term perspective to elucidate the meaning's evolution through the participant's interaction with family, community, and area outside that village. The concept of narratives in cultural psychology, such as Bruner (2002)'s narrative mode of thinking, was useful; narrative was interfering with the future, past, and present (Valsiner 2007).

Self-Meaning of Oligodactyly: Health Communication Study of People with Oligodactyly in the Village of Ulutaue, South Sulawesi, Indonesia.

A health communication of the people with oligodactyly aims at exploring the meanings associated with deformities of physical organs in fingers and/or toes from birth. This study discusses how fifteen people with oligodactyly in the village Ulutaue, South Sulawesi, Indonesia, construct themselves having physical abnormalities and physical organs different from those of other people through communicating with the surrounding environment. This research uses a subjective interpretive method with a health communication approach. The results explain that the people with oligodactyly are as the subjects and are considered to have their self-meaning, including the meaning of the physical abnormalities with the positive and negative self, the physical organ limitations with the self-meaning of feel ashamed, worthy to be pitied, will to work hard, patience and encouragement. The physical organ abnormalities provide a "scary, goose-bumpy, pity, and disgusting" image for the people who see them. To feel as "like anything" becomes the basis for the appearance of subjective meanings of every action in constructing oneself.

Extremity Findings of Methotrexate Embryopathy.

Background: Methotrexate (MTX) is widely used as an immunosuppressant, chemotherapeutic, and abortifacient agent. It is also a potent teratogen, and intentional or unintentional exposure during pregnancy is associated with heterogeneous birth anomalies. Methods: We retrospectively reviewed a cohort of patients who presented to our clinic with limb anomalies in the setting of MTX embryopathy. Results: In our case series, we describe 7 cases of patients who had limb anomalies with heterogeneous functionality, from severely debilitating to completely asymptomatic. Most of the upper extremity anomalies in our group were managed conservatively. Conclusions: Methotrexate embryopathy is a rare but clinically important entity with phenotypic and functional variability. This series underscores the need for proper counseling of patients and raises concern regarding using this medication for the purpose of abortion.

A novel mutation in SMOC1 and variable phenotypic expression in two patients with Waardenburg anophthalmia syndrome.

Waardenburg anophthalmia syndrome (WAS) is a rare disorder that mostly affects the eyes and distal limbs. In the current study we reported two Iranian patients with WAS. The first case was a 26-year-old girl with unilateral anophthalmia, bilateral camptodactyly and clinodactyly in her hands, oligodactly in her left foot and syndactyly of the second to fifth toes in her right foot. She also had severe hearing loss in both ears. The second case was a 12-year-old boy with bilateral anophthalmia, camptodactyly in his right hand, oligodactyly in his foot, clubfoot, and cryptorchidism. Both patients were mentally normal. To detect the causative mutation all exons and exon-intron boundaries of SMOC1 gene were sequenced in patients and other normal family members. We found a homozygous missense mutation (NM_001034852.2(SMOC1):c.367T > C) in exon 3 of SMOC1 gene in both patients. As the mutation segregated with the disease in the family, it should be the causative mutation. Our study extended the mutation spectrum of SMOC1 gene related to WAS.

Genetic vulnerabilities to prenatal alcohol exposure: Limb defects in sonic hedgehog and GLI2 heterozygous mice.

BACKGROUND: Genetic factors influence the physical and neurobehavioral manifestations of prenatal alcohol exposure (PAE). Animal models allow the investigation of specific genes that confer vulnerability to, or protection from, birth defects associated with fetal alcohol spectrum disorders (FASDs). The objective of the present experiments was to determine if genetic alterations in the Sonic Hedgehog (Shh) signaling pathways affect the vulnerability to PAE-induced skeletal defects involving the forelimbs and/or hindlimbs. METHOD: Wild-type C57BL/6J female mice were bred with males in which one copy of the Shh or Gli2 genes had been knocked out, to produce litters with both wild-type (+/+) and heterozygous (+/-) embryos. Alcohol doses (two injections of 2.9 g/kg, 4 hours apart) or vehicles were administered starting at gestational day (GD) 9.25, 9.5, or 9.75, a critical exposure time for inducing limb defects. Limb defects were examined at GD 17 using a dysmorphology scale based on abnormalities ranging from increased interdigital spacing to the deletion of multiple fingers and the ulna. RESULTS: Alcohol treatment caused a high incidence of forelimb defects, particularly on the right side, that was higher in Shh+/- and Gli2+/- fetuses compared to wild-type fetuses. Dysmorphology scores were also significantly higher in the Shh+/- and Gli2+/- mice. CONCLUSIONS: These results extend previous findings demonstrating enhanced sensitivity to PAE-induced craniofacial dysmorphology and support the hypothesis that genetic alterations in the Shh signaling pathway influences the vulnerability to alcohol-induced birth defects. Moreover, these results emphasize the importance of understanding the interactions between genes and prenatal exposure to alcohol or other teratogens. Birth Defects Research 109:860-865, 2017. © 2017 Wiley Periodicals, Inc.

Oligodactyly with Thumb.

BACKGROUND: Oligodactyly of the hand is one of the rarest congenital anomalies of upper extremities and defined as the presence of fewer than five fingers on a hand. Although it usually occurs in association with hypoplasia or absence of ulna, it can occur without abnormality of the forearm bones. The purpose of this study is to present clinical features and radiographic characteristics of hand oligodactyly with thumb. METHODS: Five patients of oligodactyly with thumb who showed normal forearm bones, were evaluated. Two patients had threefingered hand with thumb, and three had two-fingered hand with thumb. We analyzed associated abnormalities of carpal and metacarpal bones and measured the lengths of radius and ulna, and width of the wrist on the simple radiographs. We also devised new classification system of oligodactyly based on the thumb deformities and locations of missing digits. RESULTS: Syndactyly among fingers was associated in four patients, clinodactyly caused by delta bone in one, hypoplasia of the thumb in one, camptodactylies in one, symphalangism in one, and radial head dislocation in one. Considering the abnormalities of the carpal bones, the missing digits were presumed to be ulnar-sided digits in two patients, central digits in one patient and both ulnar-sided and central digits in two patients. In patients with missing of central digits, an adjacent metacarpal was hypertrophied. Although the ulnar variances were within normal range, the average lengths of radius and ulna were 6% and 5% shorter than those of contralateral normal side. The average width of the wrist was 9% narrower than that of contralateral normal side. CONCLUSIONS: Syndactyly and hypertrophied metacarpal were most commonly observed findings in the oligodactyly with thumb. Although oligodactyly with thumb may be a type of ulnar longitudinal deficiency, however, it can also be a type of central deficiency or combined type of ulnar longitudinal deficiency with central deficiency or radial longitudinal deficiency. We suggest a classification system of oligodactyly with thumb based on locations of missing digits and associated thumb deformities.

Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability.

KEY CLINICAL MESSAGE: We report on three related Congolese popliteal pterygium syndrome (PPS) patients concordant only for the skinfold over the toenail. Mutation analysis revealed that the three affected individuals carried a heterozygous missense mutation in the Exon 4, NM_006147.2:c.250C>T; p.Arg84Cys. This is the first molecularly confirmed PPS family from central Africa.