Extremity anomalies associated with Robinow syndrome.

Robinow syndrome, a rare genetic disorder, is characterized by skeletal dysplasia with, among other anomalies, extremity and hand anomalies. There is locus heterogeneity and both dominant and recessive inheritance. A detailed description of associated extremity and hand anomalies does not currently exist due to the rarity of this syndrome. This study seeks to document the hand anomalies present in Robinow syndrome to allow for improved rates of timely and accurate diagnosis. A focused assessment of the extremities and stature was performed using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnosis consistent with dominant Robinow syndrome or recessive Robinow syndrome were evaluated. All patients had limb shortening, the most common of which was mesomelia; however, rhizomelia and micromelia were also seen. These findings are relevant to clinical characterization, particularly as Robinow syndrome has classically been defined as a "mesomelic disorder." A total of eight distinct hand anomalies were identified in 12 patients with both autosomal recessive and dominant forms of Robinow syndrome. One patient did not present with any hand differences. The most common hand findings included brachydactyly, broad thumbs, and clinodactyly. A thorough understanding of the breadth of Robinow syndrome-associated extremity and hand anomalies can aid in early patient identification, improving rates of timely diagnosis and allowing for proactive management of sequelae.

Aarskog-Scott syndrome: clinical and molecular characterisation of a family with the coexistence of a novel FGD1 mutation and 16p13.11-p12.3 microduplication.

Aarskog-Scott syndrome (AAS), also known as facio-genital dysplasia or faciodigitogenital syndrome, is a rare genetic disorder clinically characterised by facial, limb and genitalanomalies. Although also autosomal dominance and recessive patterns have been reported, up to now, only an X linked form associated to mutations of the FGD1 gene has been recognised as causative for this syndrome.In this case report, we describe a large Italian family in which three members across three generations show classical features of the syndrome. The youngest patient, the proband, and his mother were both molecularly studied and characterised for the not previously reported variant c.1828C>T (p. Arg610*) in the FGD1 gene but with the classic phenotype of AAS. Additionally, both the proband and his mother present a 2.5 Mb 16p13.11-p12.3 microduplication, a genetic variant still unclear for the phenotypic consequences: the co-occurrence of the two rare conditions is discussed for the possible clinical significance.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Funcionalidad de prótesis de mano impresa en 3D en adolescentes con amputación congénita parcial de mano: una serie de casos / 3D-printed hand prostheses function in adolescents with congenital hand amputation: a case series

Resumen: Objetivo: Describir el efecto de la prótesis impresa en 3D Cyborg Beast en la funcionalidad de miembros superiores (MMSS) en adolescentes con amputación congénita parcial de mano. Casos Clínicos: Se seleccionaron 5 pacientes entre 12 y 17 años con amputación congénita parcial de mano en el Instituto Teletón Santiago. Los pacientes fueron entrenados en el uso de la prótesis por 4 sesiones. Se evaluó la función basal (sin prótesis), al mes y los 4 meses de uso de la prótesis con la pauta Bilan 400 points modificada y la percepción de funcionalidad de MMSS sin y con prótesis con la "Upper Extremity Function Index (UEFI)". Al mes y 4 meses de uso, el porcentaje de cambio para funcionalidad de mano fue de -11% y -4% para la extremidad no afectada y de -9% y -2% para la afectada. El porcentaje de cambio para la percepción de funcionalidad de MMSS fue de -62%. Conclusiones: El uso de la prótesis de mano Cyborg Beast no fue una solución funcional para los 5 pacientes incluidos en este estudio. Futuras investigaciones son necesarias para poder mejorar la funcionalidad de estos diseños de prótesis impresa en tecnología 3D.

Abstract: Objective: To describe the effect of the 3D-printed Cyborg Beast prosthesis on upper limbs function in adolescents with congenital hand amputation. Clinical Cases: Five patients aged between 12 and 17 years, with congenital hand amputation were selected. All patients were from the Teletón Institute in Santiago, Chile. The patients were trained for prosthesis use in four sessions. Hand function was evaluated without prosthesis, at 1 and 4 months of use with the modified Bilan 400 points scale, and upper limb function perception was evaluated with the 'Upper Extremity Functional Index (UEFI)'. At 1 month and 4 months of use, the percentage change for hand functionality for the unaffected limbs was between -11% and -4%; and -9% and -2% for the affected limb. The percentage change for the upper limbs perceived function was -62%. Conclusions: The use of the 3D-printed Cyborg Beast prosthesis was not a functional solution for the 5 patients included in this study. Future research is needed to improve the functionality of these types of 3D-printed hand prostheses.

Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion.

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.

Duplication of 10q24 locus: broadening the clinical and radiological spectrum.

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.

Functional Assessment of Children and Adolescents with Symbrachydactyly: A Unilateral Hand Malformation.

BACKGROUND: We studied children and adolescents with symbrachydactyly to determine whether hand function depends on digit opposability and whether scores for function and quality-of-life measures differ from population norms. METHODS: Participants were grouped on the basis of hand morphology: Group A lacked opposable digits, and Group B had ≥2 digits that were opposable. The groups were compared with each other and with norms with respect to pinch strength, the performance of bimanual activities and in-hand manipulation, and questionnaires regarding psychosocial status and the ability to perform activities of daily living (ADLs). Participants and parents also rated the appearance and function of the hand. RESULTS: Pinch strength was higher for participants in Group B (4.1 compared with 2.4 kg; p = 0.008), but the groups did not differ with respect to the proportion of participants outside of pinch norms. Participants in Group B were more likely to actively use their affected hand to perform bimanual activities (p ≤ 0.0009), and to use normal or supination strategies to accomplish in-hand manipulation (p = 0.031). The groups did not differ in the proportion of ADLs rated "difficult" or "impossible," and both groups tested within normal limits for psychosocial function. Participants from both groups and their parents rated their satisfaction with hand appearance and function similarly high. CONCLUSIONS: Participants with ≥2 opposable digits incorporated their hand better in bimanual activities and used more effective strategies to accomplish in-hand manipulation than those who did not. These groups reported no difference in the ability to perform ADLs or with psychosocial function, which was within the normal range. Children and adolescents with symbrachydactyly demonstrated and reported a high level of function in all domains of validated function tests. This study provides information to help parents of children with a unilateral hand malformation understand their child's potential function, and assist surgeons with recommending treatment. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus.

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.

FATCO Syndrome (Fibular Aplasia, Tibial Campomelia, Oligosyndactyly with Talar Aplasia). A Case Study.

FATCO syndrome consists of fibular hemimelia, tibial campomelia and oligosyndactyly. FATCO syndrome can also be associated with other congenital anomalies; therefore, every case needs thorough evaluation so as to make the management of the patient easier. A few cases of this syndrome have been described in literature but only two cases have been reported in India so far. We present a 3-year-old male child born of a non-con-sanguinous marriage with FATCO syndrome and ipilateral talar aplasia without any other congenital anomalies.

Short stature, unusual face, delta phalanx, and abnormal vertebrae and ribs in a girl born to half-siblings.

Delta phalanx is a rare abnormality typically associated with additional features. We describe a patient with a phenotype resembling Catel-Manzke syndrome, but with delta phalanx and abnormal vertebrae and ribs. The patient was the only child of half siblings born with a marked prenatal growth deficiency. At 10 years of age, she had a short stature, long face, long and tubular nose with small alae nasi, high palate, short and broad thorax, and short index fingers with radial deviation. There were hyperpigmentations following Blaschko's lines. Radiology showed a proximal delta phalanx in the index finger of hands, abnormal vertebrae, and fused and small ribs. GTG-Banding karyotype and microarray analysis yielded normal results. Exome sequencing identified 25 genes that harbored homozygous variants, but none of these is assumed to be a good candidate to explain (part of) the phenotype. The here described patient may have a new condition, possibly following an autosomal recessive pattern of inheritance, although due to the high degree of consanguinity a compound etiology of the phenotype by variants in various genes may be present as well.

Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails.

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.

Postoperative Growth in Radial Polydactyly: A Clinical Study.

PURPOSE: This study was designed to evaluate thumb growth after surgical management of a duplicate thumb and investigate its developmental pattern. METHODS: We compared the thumbs and index fingers of 486 normal children (aged 1-18 y) (group A) with 15 children showing radial polydactyly (group B). All duplicate thumbs were treated with excision of the radial thumb and reconstruction of the ulnar thumb. Radiographs of groups A and B were used to compute the thumb-to-index finger length ratio and width ratio, and the thumb-to-index finger phalanx length ratio and phalanx width ratio. RESULTS: In group A, the length ratio, width ratio, phalanx length ratio, and phalanx width ratio did not change with age, and remained constant in males and females. In group B, after an average follow-up period of 41.0 months, the original findings were also similar to the final ratios. In group B, only the phalanx width ratio was obviously smaller than normal. CONCLUSIONS: A permanent developmental stability exists between the thumb and the index finger, even in patients with radial polydactyly. The development of the retained digit is not influenced by the ablation of the extra digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Morphology and Mobility of the Reconstructed Basilar Joint of the Pollicized Index Finger.

PURPOSE: To evaluate outcome and function of the reconstructed basilar thumb joint after index finger pollicization in patients presenting congenital thumb deficiency. METHODS: Plain radiographs and 4-dimensional dynamic volume computed tomography scan were used to evaluate the outcome of 23 pollicizations performed on 14 children between 1996 and 2009. The mean follow-up was 8 years. Patients performed continuous movements of thumb opposition during the imaging studies. Four-dimensional scan images made it possible to visualize mobility within the reconstructed joint. RESULTS: In 14 cases, union occurred in the metacarpal head/metacarpal base interface. In the 9 other cases, there was a nonunion at this interface. The reconstructed joint was mobile in 20 cases, including 3 in which there was also mobility at the site of the nonunion. In 3 cases in our series, mobility was present only at the site of the nonunion, between the base and the head of the second metacarpal. Remodeling and flattening out of the metacarpal head occurred in 16 of 23 cases. The transposed metacarpal head remained spherical in 7 cases. CONCLUSIONS: The reconstructed joint adapts, both morphologically and functionally, allowing movement on all 3 spatial planes. Existing mechanical constraints on the reconstructed joint may explain its remodeled appearance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.