Thumb Abnormalities Research Articles

Townes-Brocks Syndrome Revealed by Kidney Gene Panel Testing

Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with SALL1 (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of SALL1 variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features. A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in SALL1. Data including age, features, and disease progression were collected. Of 35,044 samples, P or LP variants in SALL1 were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both a priori TBS diagnoses and the traditional "triad." Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that SALL1 P/LP variants could be a consequential contributor to monogenic kidney disease.

THROMBOCYTOPENIA, HYPOGAMMAGLOBULINEMIA, AND POOR VACCINE RESPONSE IN A PATIENT WITH TAKENOUCHI-KOSAKI SYNDROME

<h3>Introduction</h3> Takenouchi-Kosaki Syndrome (TKS) is a rare congenital developmental disorder characterized by thrombocytopenia, facial abnormalities, and varied multisystemic anomalies including immunodeficiency. Heterozygous deficiency of CDC42, an intracellular signaling GTPase, has been found in all TKS patients described to date. The immunological phenotypes of TKS patients are heterogeneous: recurrent infections have been noted in some patient series but with variable penetrance. Herein we describe a case of TKS causing hypogammaglobulinemia, B-cell lymphopenia, and poor vaccine response. <h3>Case Description</h3> A fifteen-year-old girl with history of developmental delay, multiple congenital defects, and lymphedema was referred to the immunology clinic for evaluation of recurrent ear infections that began at 3 months of age requiring tympanostomy tube placement at 18 months. Her physical exam was notable for abnormal facies, scoliosis, strabismus, abnormal thumbs, and unilateral lymphedema. Her laboratory evaluation revealed macrothrombocytopenia, mild leukopenia with low T-cells and markedly low B-cells by flow cytometry, and notably low IgA (11.7, RR 69 – 309) and IgG (423, RR 613 – 1295). She had a poor response to a full course of PCV7 with PPSV23 booster (9 of 23 > 1.3). Whole exome sequencing identified a heterozygous p.Y64C mutation in CDC42 consistent with TKS. <h3>Discussion</h3> The Y64C mutation in CDC42 is a TKS Group I lesion causing ineffective intracellular signaling, resulting in <i>in vitro</i> defects including abnormal cellular proliferation and disruption of cell polarity. Actin remodeling disorders such as Wiskott-Aldrich Syndrome and TKS should be considered in patients with immunodeficiency and congenital thrombocytopenia.

Frequency Determination of c.1115_1118delTTGG and c.3788_3790delTCT FANCA Gene Mutation in North of Khyber Pakhtunkhwa (KPK) Pakistan Fanconi’s Anemia Population

Background: This study aimed to assess the frequency determination of c.1115_1118delTTGG and c.3788_3790delTCT Fanconi's anemia A gene (FANCA) gene mutation in the North of Khyber Pakhtunkhwa (KPK) Pakistan Fanconi’s Anemia Population.&#x0D; Materials and Methods: A cross-sectional study was conducted at Khyber Medical University, Peshawar, Pakistan. For the Exon 13 mutation c.1115_1118delTTGG, the amplification-refractory mutation system polymerase chain reaction (ARMS PCR) was developed. Sanger sequencing confirmed the ARMS PCR results for Exon 13 and found an exon 38 mutation of the FANCA (Fanconi anemia complementation group A) gene (c.3788_3790delTCT). Sanger sequencing results analyzed on Bio edit sequence aligner software confirmed the results of PCR. The four incidental single nucleotide polymorphisms (SNPs) discovered were examined in several variation databases.&#x0D; Results: The mean age for the patients was 9.68±3.02 years, with an age range of 5–16 years. Pedigree analysis of Fanconi Anemia patients revealed an autosomal recessive pattern of inheritance. Physical characteristics such as skeletal abnormalities, specifically thumb abnormalities and Fanconi's facies, are distinctive diagnostic features of FA. Pedigrees also showed bone marrow hypoplasia in 65% of patients and red cell aplasia in 6%. PCR results from all samples revealed tahat none of them had the Exon 13 mutation. In addition, none of the samples had the Exon 38 mutation. Four SNPs were found in the Sanger sequencing. Two of them were in the intron 12 region, one in each of Exons 13 and 38.&#x0D; Conclusion: Results show that mutations in Exon 13 and Exon 38 of the FANCA gene are uncommon in our Pakistani FA population. SNPs established in the Pakistani population of Khyber Pakhtunkhwa (KPK) province have not been reported before.

Identification of a novel TBX5 c.755 + 1G > A variant and related pathogenesis in a family with Holt-Oram syndrome.

The proband with congenital heart disease and abnormal thumb was clinically diagnosed as Holt–Oram syndrome (HOS). A novel variant, T‐box transcription factor 5 (TBX5) c.755 + 1 G > A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III‐1), her brother (III‐2), and her mother (II‐2) were 50%, 48.3%, and 38.1%, respectively, indicating that III‐1 and III‐2 harbored heterozygous variants, while II‐2 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal TBX5 transcripts. Reverse transcription‐quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated TBX5 expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.

1: Eye Tracking Analysis as a Means of Evaluating Aesthetic Result Following Toe to Thumb Transfers: A Pilot Study

Purpose:Exceptional functional results can be obtained with toe to thumb transfers; however objective measures to evaluate the aesthetic outcome of a toe to thumb transfers remains elusive. Aesthetic evaluation of a reconstruction when performed by external raters or the patient, may be influenced by expert knowledge, emotional antecedent, or ethnic or regional bias. In this study, we were interested in determining the observers’ instantaneous, reflexive responses to the toe to thumb transfer as determined by eye-tracking analysis.Methods:13 patients with unilateral great toe to thumb transfers were photographed using a standardized technique. None had undergone secondary procedures that changed the appearance of the transferred toe. Both hands were photographed side by side in each image. A dorsal and palmar image was taken, producing 26 photos in total. 40 observers (Average age 41.39, 14-65 yo, 18 males, 22 females), blinded to the procedure, were asked to evaluate each image for symmetry between the hands. An infrared eye-tracking camera continuously recorded their eye movements. Participants were allowed to evaluate each image for 6 seconds. Data was evaluated to determine the percent of time that was devoted to evaluating each portion of the photograph. The percent time spent in each of the lookzones was recorded.Results:i) Observers spent an average of 17.7% of their time evaluating the reconstructed thumb compared to the entire bilateral hand. This was on average 63% more time looking at the reconstructed thumb compared to the normal control thumb. (p value<0.01) ii) Observers spent 43.9% of the time looking at the reconstructed thumb compared to the entire hand of the same side. They spent 31.6% of the time looking at the normal control thumb compared to the entire hand of the same side (p value<0.01, mean 0.36 seconds on the abnormal thumb (SD 0.439)), vs. mean 0.22 seconds on normal control thumb (SD 0.305); mean 0.82 seconds on abnormal hand (SD 0.45), mean 0.69 seconds on normal contralateral hand (SD 0.423); mean 0.74 on entirely normal bilateral hand (SD 0.41)). iii) Areas of significant attention as visualized by heatmaps representing where observers focus their attention include abnormal nailbed and scar tissue at the junction between the toe and native hand skin.Conclusion:The technique described above may represent a novel and objective technique for quantifying observers’ gaze with respect to toe to thumb reconstructions and the un-altered contralateral thumb. It could be applied to other areas of hand reconstruction to help determine aesthetic outcomes. The present pilot suggests that symmetric nail size may be an area of importance for creating the sense of aesthetic success. Incorporation of this data into surgical counseling may assist the patient and medical team focus on surgical-decision making priorities.

A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies.

In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Combining mouse genetics and invivo ribosome profiling, we observe limb-patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos, and we uncover selective translational changes of transcripts that controlling limb development. Surprisingly, both loss of p53, which is activated by RP haploinsufficiency, and augmented protein synthesis rescue these phenotypes. These findings are explained by the finding that p53 functions as a master regulator of protein synthesis, at least in part, through transcriptional activation of 4E-BP1. 4E-BP1, a key translational regulator, in turn, facilitates selective changes in the translatome downstream of p53, and this thereby explains how RP haploinsufficiency may elicit specificity to gene expression. These results provide an integrative model to help understand how invivo tissue-specific phenotypes emerge in ribosomopathies.

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant.

Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype–phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.

Holt–Oram Syndrome Associated with Complex Congenital Heart Disease: A Rare Case Presentation and Literature Review

BACKGROUND: First described by Holt and Oram in 1960 in a four-generation family with atrial septal defects and thumb abnormalities, is an inherited disorder characterized by abnormalities of the upper limbs and heart. This syndrome is characterized by upper extremity malformations involving radial, thenar, or carpal bones. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. About 75% of individuals with Holt–Oram syndrome (HOS) have a congenital heart malformation which may include an atrial or ventricular septal defect or heart block. In rare cases, the syndrome can affect other organs and systems which can be life threatening.&#x0D; CASE REPORT: Here, we present a newborn with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited bilateral supination due to radioulnar synostosis, and associated with complex heart disease and hypoplastic tricuspid valve.&#x0D; CONCLUSION: In our case HOS is associated with complex congenital heart defects including atrial septal defect, ventricular septal defect with hypoplastic tricuspid valve. Based on the listed literature we didn’t find any other case where tricuspid valve was affected.

Analysis of Causes for Congenital Ulnar Deviated Thumbs at the Distal Phalanx Level in 157 Thumbs

To investigate anatomic abnormalities causing a congenital ulnarly deviated thumb at the distal phalanx. A total of 122 children with 157 congenital ulnarly deviated thumbs at the distal phalanges were reviewed, including those with isolated deformity or polydactyly. We analyzed the incidence and characteristics of the underlying anatomic abnormalities as well as the differential diagnoses. Three main causes of an ulnarly deviated thumb were observed. Abnormal hypertrophic epiphyses were found in 96 thumbs. An extra phalanx lying between the normal proximal and distal phalanges was found in 59 thumbs. A previously undescribed cause was found in 2 thumbs with Wassell IV polydactyly, in which an obliquely angled articular surface of the proximal phalanx manifested with ulnar deviation at the interphalangeal joint. Radiographic analysis showed that in cases with abnormal epiphyses, the epiphysis was in good apposition and good alignment with its relevant distal phalanx; the distance from the abnormal epiphysis to the phalanx was usually less than 1 mm. In contrast, in cases of extra phalanges, the distance from the epiphysis to the phalanx averaged more than 2 mm and there was poor apposition between the distal phalanx and the extra bone. Abnormal hypertrophic epiphysis and triphalangeal thumb are the 2 main causes of a congenital ulnarly deviated thumb. A distance of more than 2 mm between the abnormal bone and the distal phalanx suggests a triphalangeal thumb. Therapeutic IV.

Feasibility of Ultrasound in Infant Wrist and Thumb Imaging.

To determine the feasibility of ultrasound (US) in infant lateral carpal and base-of-the-thumb imaging. We hypothesized that US would be a practical modality for visualizing the unossified structures. Institutional review board approval was obtained for this single-center pilot study. Healthy infants aged 12 months or younger were enrolled. Ultrasound examinations of the distal radial epiphysis through the first metacarpal were performed with a high-frequency transducer. Ultrasound evaluations of the base of the thumb were performed in 18 healthy infants (mean age ± SD, 13.8 ± 9.1 weeks; 44% female). Assuming an elliptical shape, the mean areas of the scaphoid and first metacarpal epiphysis measured 0.85 ± 0.19 and 0.44 ± 0.087 cm2 , respectively. The mean areas of the trapezium and ossified first metacarpal as approximate rectangular shapes measured 0.23 ± 0.069 and 0.49 ± 0.16 cm2 . A perimeter tracing was also used as an alternative area calculation. The mean trapezium area-to-scaphoid area ratio (0.28 ± 0.10) showed less variability compared to the first metacarpal epiphysis area-to-scaphoid area ratio (0.55 ± 0.20) or first metacarpal area-to-scaphoid area ratio (0.64 ± 0.31). Our data suggest that US is well suited for the evaluation of the lateral carpus and base of the thumb in young infants. These data serve as a reference to which wrist and thumb abnormalities can be compared.

Variable prenatal presentation of Pfeiffer syndrome: Suggested aids to prenatal sonographic diagnosis

Our purpose was to describe and compare the cranial and extracranial abnormalities of Pfeiffer syndrome on prenatal imaging with postnatal or postmortem findings, which may help in prenatal diagnosis of Pfeiffer syndrome (PS). Cases of fetuses with a confirmed diagnosis of PS over a 4-year period (2012-2016) were retrospectively reviewed. Prenatal imaging findings, postnatal, or postmortem investigations and genetic test results were analyzed. Four fetuses were ascertained, 3 with prenatal sonographic findings compatible with PS and one only diagnosed at postmortem. Cases were referred between 22 and 24weeks' gestation. Three of the 4 cases were terminated, and details of postmortem/postnatal examination were available in all. There was variable presentation of features. Craniosynostosis was present in 3 cases, but only detected prenatally in 2. Extracranial signs included abnormalities of thumbs and/or big toes, detected prenatally in 3 of the 4 cases. A sacral appendage and vertebral or coronal clefts were present at postmortem in 3 cases but only detected prenatally in one. A cartilaginous tracheal sleeve was detected at postmortem in all 3 cases but not detected by prenatal ultrasound. Other findings included ventriculomegaly, posterior fossa, and facial anomalies. Molecular testing revealed mutations of the fibroblast growth factor receptor 2 (FGFR2) gene in all cases. Pfeiffer syndrome has a highly variable phenotype, and the absence of craniosynostosis on prenatal US does not exclude the diagnosis. Presence of abnormal thumbs and big toes, a sacral appendage, vertebral fusions, and coronal clefts should lead to prenatal molecular testing for PS.

A Case of Three Deltas in a Fingerprint

Fingerprints begin forming at about the 6th to the 13th week of gestation. A number of factors determine the print pattern in the womb, including the density of the amniotic fluid surrounding the foetus, the size of the foetus, the friction in the womb, the location in the womb amongst others. Once developed the pattern remains constant throughout life. Basically there are three main patterns; The Loop, which rise up and loop back around, continuing on the same direction it started from and it accounts for about 70% of all fingerprints, Arches look like waves that rise and fall on the same fingerprint pattern, accounting for 5% whiles the Whorls appear as circular patterns accounting for 25%. The loop has only one delta, the Arch no delta with the Whorl pattern having two deltas. In the case presented here, a young man of 30 years, who is physically fit and normal without any significant clinical condition apart from a developmental defect of the right thumb which makes it different from the left thumb. From the ten fingerprint patterns taken with the aid of a scanner from the subject, only the abnormal right thumb of the subject with a whorl fingerprint pattern has three deltas which are extremely uncommon and quite different to the traditional, widely known two deltas seen in all whorl patterns in fingerprints. Fingerprint deltas are only present in loops and whorls. There are basically four types of fingerprint whorls. The plain with two deltas, central pocket with two deltas, the double loop whorls with two deltas and accidental whorls which have two or more deltas. Theoretically, less than 1 in 1000 people has these extremely rare fingerprints. The three deltas in a fingerprint whorl pattern may exist in accidental whorls, but no mention is made of it in plain whorls which make this case perhaps the first ever of a known plain whorl with three deltas. This feature is very uncommon in normal patterns. In this case the thumb of this young man has developed abnormally in the womb and has a whorl pattern with three deltas. It is imperative this pattern is taken into consideration when evaluating or interpreting fingerprints. Though the number may be statistically small, it is still essential this is taken into account in manual and especially when using automatic fingerprint identification software to evaluate known and unknown fingerprints.

Defining Features of the Upper Extremity in Holt-Oram Syndrome

To investigate the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS). One hundred fourteen involved extremities in 62 patients with a diagnosis of HOS were identified at 3 institutions. Medical records and radiographs were evaluated. Radial longitudinal deficiency and thumb hypoplasia were classified according to the modified Bayne and Klug classification and Blauth classifications, respectively, when possible. Other unusual or distinguishing characteristics were catalogued. There was bilateral involvement in 84% of patients. The forearm was involved in 81% of the extremities and a shortened distal radius (Bayne and Klug type I RLD) was the most commonly identified forearm anomaly (40%). Radioulnar synostosis was present in 15% of the extremities, all in the proximal forearms with reduced radial heads. Thumb aplasia (Blauth type V hypoplastic thumb) was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. Twenty-seven percent of abnormal thumbs affected were not classifiable according to the Blauth classification, and 19% of involved thumbs (hypoplastic or absent) had first-web syndactyly. The upper extremity in HOS differs from the typical presentation of RLD. The forearm is more often involved and may demonstrate radioulnar synostosis. The thumb is frequently unclassifiable by the Blauth classification and has first-web syndactyly. The presence of radioulnar synostosis and syndactyly of the radial 2 digits in RLD should prompt the hand surgeon to obtain a cardiac evaluation and consider genetic testing for HOS. Diagnostic III.

G407(P) Macrocytosis – a rare but serious problem!

Aims A case report to highlight the importance of macrocytosis. Methods A 7½ year old boy was referred with macrocytosis (MCV 108). He was fit and thriving child (weight, height 50th centile). History and examination was unremarkable. Bloods done 5 years ago also showed high MCV (95). Routine tests for evaluation of macrocytosis were normal. Later FBC showed thrombocytopenia, leucopenia and neutropenia. He was finally diagnosed to have Fanconi anaemia. He has been put on register for bone marrow transplant, and whole family is being tested for gene mutations. Fanconi anaemia is an autosomal recessive or X-linked form of inherited aplastic anaemia. Sixteen mutations (FA-A to FA-Q) have been identified. Hematologic findings evolve over months to years, with 70% of children developing bone marrow failure by age 10. They are at high risk for developing myelodysplastic syndrome, acute myeloid leukaemia, and squamous cell carcinoma. Characteristic congenital malformations are present in up to 70% of affected children (short stature, cafe-au-lait spots, hypopigmented spots, thumb abnormality, microcephaly, hydrocephaly, hypogonadism, developmental delay). Diagnosis is made by presence of increased chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking agents (mitomycin C or diepoxybutane). Bone marrow transplant is the only available curative treatment. Other treatment options include androgens, hematopoietic growth factors, and blood product transfusions with supportive care. Results Hb 122, WCC 8.6, Platelets 164, MCV 102 in 2011. Hb 118, WCC 5.4, Neutrophils 1.34, Platelets 130, MCV 108 in 2014. U&E, LFT, immunoglobulins, B12, Folate, Ferritin, and TFT were normal. Bone marrow biopsy revealed mild aplasia, and no myelodysplastic syndrome or leukaemia. HIV, Hepatitis screen and viral serology were negative. Fanconi Anaemia test came back positive. Conclusions Children presenting with macrocytosis should be carefully evaluated and referred to a haematologist, as it could be the first manifestation of a serious underlying bone marrow problem. Macrocytosis in age range of six months to 12 years age is MCV >90. Causes of macrocytosis include disorders of folate/B12 metabolism, liver disease, congenital heart disease, Down’s syndrome, hypothyroidism, drugs (anticonvulsants, zidovudine, hydroxyurea, immunosuppresants), myelodysplastic syndromes, bone marrow failure, and rare genetic syndromes (eg, Fanconi anaemia, thiamine-responsive megaloblastic anaemia syndrome).

Anesthetic management of a child with Diamond-Blackfan syndrome

Diamond-Blackfan anemia (DBA) is a rare congenital disorder that can pose a variety of anesthetic challenges to a clinician. A disorder of pure red cell aplasia is associated with other congenital anomalies such as craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. These anomalies are compounded by problems of iron overload and chronic steroid therapy. Anesthetic management of a child with DBA requires knowledge and skill to handle a difficult pediatric airway and a thorough understanding of the congenital heart lesion of the child and its interaction with anesthetic agents and surgery. Rarity of DBA, along with its associated problems and lack of awareness of these by the anesthesiologist, makes the occasional surgery in this population very challenging. We report a 1-year 3-month-old child, diagnosed to have DBA during infancy, posted for laparoscopic orchidopexy.

Phenotype analysis of Polish patients with mandibulofacial dysostosis type Guion-Almeida associated with esophageal atresia and choanal atresia caused by EFTUD2 gene mutations.

We present the phenotype of three unrelated Polish patients with MFD type Guion-Almeida confirmed by EFTUD2 mutations. In all of our patients, dysmorphic craniofacial features, microcephaly, thumb abnormalities, psychomotor and speech delay were described. In addition, among other major defects, esophageal atresia (EA) in one patient and choanal atresia in two of them were present. Three different mutations in EFTUD2 gene were found in presented patients. Our observations confirm the clinical heterogeneity of mandibulofacial dysostosis type Guion-Almeida and its connection with major congenital defects such as esophageal atresia and choanal atresia.

Pollicization of the index finger in Fanconi anaemia: appearances and functionality 40 years after the intervention

Fanconi anaemia (FA) is an inherited bone marrow failure syndrome resulting from disruption of a polygenic DNA damage response pathway with variable congenital and developmental abnormalities. Radial ray and thumb abnormalities are classical diagnostic features. These can vary in their clinical severity, but often have significant impact on development and hand usage in later life. Absence or severe hypoplasia of the thumbs can be surgically managed by pollicization with ante-position of the index finger. Very long term outcome and performance in adult life is not well documented. Here we illustrate functionality and appearances of the hands of a 47-year-old woman diagnosed with FA at the age of 3 years because of right thumb absence, severe hypoplasia of the left thumb and thrombocytopenia. Surgery on both hands was carried out shortly after the diagnosis. Clinical documentation from the 1960s and 1970s is unavailable. After completing school she worked in a responsible office-based position. She married, and after several years living abroad, returned to our region and is now followed up in our FA service. She has mild thrombocytopenia with a platelet count of 117 × 109/l, but otherwise normal peripheral blood cell counts with a moderately hypoplastic bone marrow. There is no evidence of mosaicism with persistent FA characteristic G2 arrest spontaneously and with low dose mitomycin C (MMC). At the age of 47 years her hands appear as illustrated. Frequent and purposeful use of the pollicized index finger generated a thenar-like bulk between the opposed index finger and the second finger. Magnetic resonance imaging illustrates the detailed anatomy. Coronal T1 images (A & B) demonstrate normal position of digits 3, 4 and 5 (A – solid arrows) with transposition of the 2nd metacarpal (A – dashed arrow) to create a pseudo 1st metacarpal. The pseudo 1st proximal phalanx (B – dashed arrow) is seen adjacent to a tissue mass placed at the site of the original location of the 2nd metacarpo-phalangeal joint (B – solid arrow). A whole forearm maximum intensity projection from fat- saturated T1 weighted images (C) clearly demonstrates the relationship between the pseudo 1st finger position (dashed arrow), and 3rd, 4th and 5th fingers (solid arrows) with interposed fat (open arrow). Her ante-positioned index fingers had excellent functionality. An illustration of her handwriting is shown in the lower panel (A – insert). To our knowledge this is the longest follow-up ever documented of a pollicization of an index finger in FA, with a very satisfactory long-term outcome.

Relationship between Malocclusion and Oral Habits

In addition to heredity, oral habits are considered important factors in the etiology of malocclusion. This study was taken to assess the relationship between Malocclusion and Oral Habits. The sample comprised of 674 orthodontically untreated subjects, 324 males (48%) and 350 females (52%) 12 to 15-year-old schoolchildren from the southern part of Italy. Orthodontic variables and oral habits including mouth breathing and swallowing pattern; thumb, finger and lip sucking; and nail biting of the patients were evaluate. Two examiners, who had been previously trained in the use of occlusal indices, screened all the schoolchildren. The chi-square and binomial test was used to evaluate the data. A total of 589 of the subjects were found to have deleterious oral habits. Nail biting was found to be the most common habit (65.5%) followed by lip sucking (42.7%), mouth breathing (28.6%), abnormal swallowing pattern (22.7%) and thumb sucking (13.2%). Positive association exist between deleterious oral habits and malocclusions; however, there is no significant relationship between the type of oral habit and malocclusions.

Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes

Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome linked to mutations in ribosomal protein (RP) genes that result in the impaired proliferation of hematopoietic progenitor cells. The etiology of DBA is not completely understood; however, the ribosomal nature of the genes involved has led to speculation that these mutations may alter the landscape of messenger RNA (mRNA) translation. Here, we performed comparative microarray analysis of polysomal mRNA transcripts isolated from lymphoblastoid cell lines derived from DBA patients carrying various haploinsufficient mutations in either RPS19 or RPL11. Different spectrums of changes were observed depending on the mutant gene, with large differences found in RPS19 cells and very few in RPL11 cells. However, we find that the small number of altered transcripts in RPL11 overlap for the most part with those altered in RPS19 cells. We show specifically that levels of branched-chain aminotransferase-1 (BCAT1) transcripts are significantly decreased on the polysomes of both RPS19 and RPL11 cells and that translation of BCAT1 protein is especially impaired in cells with small RP gene mutations, and we provide evidence that this effect may be due in part to the unusually long 5'UTR of the BCAT1 transcript. The BCAT1 enzyme carries out the final step in the biosynthesis and the first step of degradation of the branched-chain amino acids leucine, isoleucine, and valine. Interestingly, several animal models of DBA have reported that leucine ameliorates the anemia phenotypes generated by RPS19 loss. Our study suggests that RP mutations affect the synthesis of specific proteins involved in regulating amino acid levels that are important for maintaining the normal proliferative capacity of hematopoietic cells.

Connecting isolated congenital asplenia to the ribosome

Isolated congenital asplenia is characterized by the absence of a spleen at birth without any other developmental defect. Isolated congenital asplenia is a rare and life-threatening disease that predisposes patients to severe bacterial infections. The first and main genetic etiology of isolated congenital asplenia was discovered in 2013. Mutations in the gene RPSA, which encodes ribosomal protein SA, cause more than half of the cases of isolated congenital asplenia. These disease-causing mutations lead to haploinsufficiency of RPSA. Haploinsufficiency of genes encoding other ribosomal proteins have been reported to cause other developmental defects in humans, and in model organisms like the fly or the mouse. About half of the patients with Diamond-Blackfan anemia, which is a well-characterized ribosomopathy, present developmental defects such as craniofacial defects, cardiac defects or thumb abnormalities. The mechanism of pathogenesis linking mutations in ribosomal proteins, which are highly and ubiquitously expressed, to specific developmental defects remains to be elucidated. One hypothesis is that the ribosome, and ribosomal proteins in particular, regulate the expression of specific genes during development.