Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.

Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C.

BACKGROUND: Brachydactyly (BD) type C is a rare form of familial BD caused by GDF5 mutations. Some of the affected children have severe clinodactyly requiring surgery. The literature is limited to case reports. PATIENTS AND METHODS: The current retrospective study included 15 Saudi Arabian families with 42 affected children seen by the author for 25 years. A total of 23 digits (in 23 hands) underwent surgical correction of clinodactyly using a closing wedge osteotomy. The current study reports on the genetics, clinical presentation, radiological features, and midterm outcome of surgery. RESULTS: Genetic analysis was done in 6 families and confirmed the presence of 2 novel missense mutations (p.Met173Val in 3 families and p.Thr203Asn in 3 families) in the GDF5 gene. All cases in the study group demonstrated the classical clinical and radiographic features of BD type C. However, only 1 hand showed all the features of angel-shaped bony defect. The clinodactyly defect was mostly observed in the index or middle fingers. Surgery for the clinodactyly defect was only done if there was finger overlap. Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome. CONCLUSIONS: This study represents the largest reported series of children undergoing surgery for correction of BD type C clinodactyly with a uniform technique performed by a single surgeon. The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking.

One Pedicled Superficial Temporal Artery Hair-bearing Flap to Reconstruct Three Different Anatomical Areas of the Burnt Face: A Personal Technique.

ABSTRACT: Reconstruction of the burnt face is a challenge. In men, the best option to hide facial scars and get rid of the grafted facial appearance is to use the superficial temporal artery hair-bearing flap. In the literature, the superficial temporal artery flap hair-bearing flap has been used to reconstruct one facial anatomical area in men such the eyebrows, the beard, or the mustache area. In this communication, the author describes a personal technique that allows the use of one pedicled superficial temporal artery hair-bearing flap to reconstruct both eyebrows and improve the grafted appearance of the upper/lower lips post the release and graft of burn contractures. The technique will be demonstrated by a case presentation.

Autozygome and high throughput confirmation of disease genes candidacy.

PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Rubinstein-Taybi syndrome in a Saudi boy with distinct features and variants in both the CREBBP and EP300 genes: a case report.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) Type 1 (OMIM 180849) is characterized by three main features: intellectual disability; broad and frequently angulated thumbs and halluces; and characteristic facial dysmorphism. CASE PRESENTATION: We report on a Saudi boy with RSTS Type 1 and the following distinct features: a midline notch of the upper lip, a bifid tip of the tongue, a midline groove of the lower lip, plump fingers with broad / flat fingertips, and brachydactyly. The child was found to be heterozygous in the CREBBP gene for a sequence variant designated c.4963del, which is predicted to result in premature protein termination p.Leu1655Cysfs*89. The child and his father were also found to be heterozygous in the EP300 gene for a sequence variant designated c.586A > G, which is predicted to result in the amino-acid substitution p.Ile196Val. CONCLUSION: Our report expands the clinical spectrum of RSTS to include several distinct facial and limb features. The variant of the CREBBP gene is known to be causative of RSTS Type 1. The variant in the EP300 gene is benign since the father carried the same variant and exhibited no abnormalities. However, functional studies are required to investigate if this benign EP300 variant influences the phenotype in the presence of disease-causing CREBBP gene mutations.

Cenani-Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways.

Cenani-Lenz (C-L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features. Most cases are caused by homozygous and compound heterozygous missense and splice mutations of the LRP4 gene. Currently, the syndrome carries one OMIM number (212780). However, C-L syndrome-like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1-FMN1 locus, as well as FMN1 mutations. Surprisingly, patients with C-L syndrome-like phenotype caused by APC truncating mutations have no polyposis despite the increased levels of ß catenin. The LRP4 and APC proteins act on the WNT (wingless-type integration site family) canonical pathway, whereas the GREM-1 and FMN1 proteins act on the bone morphogenetic protein (BMP) pathway. In this review, we discuss the different mutations associated with C-L syndrome, classify its clinical features, review familial adenomatous polyposis caused by truncating APC mutations and compare these mutations to the splicing APC mutation associated with syndactyly, and finally, explore the pathophysiology through a review of the cross talks between the WNT canonical and the BMP antagonistic pathways.

Fractures of the Base of the Proximal Phalanx in Children: Remodeling of Malunion in the Radioulnar Plane With a Diaphyseal Axis-Metacarpal Head Angle of 156° to 163°.

BACKGROUND: The diaphyseal axis-metacarpal head angle (DHA) measures the angle between the axis of the proximal phalanx and the center of the metacarpal head. In unfractured fingers, the normal DHA ranges from 177.1° to 180.0°. The angle may be used to quantify the degree of lateral displacement of pediatric fractures of the base of the proximal phalanx. Previous authors have shown that if the postreduction x-rays show an angle greater than 169° remodeling with normalization of the DHA is expected to occur in children. The degree of remodeling of more severe angulations is unknown. PATIENTS AND METHODS: This is a retrospective study (over the last 5 years) that identified 8 late referrals (4-6 weeks after injury) of inadequately reduced pediatric fractures of the base of the proximal phalanx with a postreduction DHA of 156° to 163°. At the time of presentation to the author, there was lateral deviation of the finger, and the fracture site was not tender, indicating malunion. All patients were offered surgery, but this was refused by the parents. Follow-up appointments to the clinic were made, and the DHAs were serially measured to investigate the degree of remodeling. RESULTS: Seven patients had normalization of the DHA (ie, an angle >177°) between 9 and 18 months. In the remaining patient, the DHA was 175.7° at 2 years. CONCLUSIONS: The current study shows adequate remodeling of severe residual angular deformities (DHA of 156°-163°). The clinical implication of this finding is regarding late referrals with no tenderness at the fracture site. In these cases, refracturing usually requires general anesthesia. Our study shows that patients may be given the option of conservative management awaiting remodeling.

Flexor Tendon Reconstruction: Active Range of Motion After the First Stage of Silicone Rod Insertion.

PURPOSE: In the first stage of flexor tendon reconstruction, a silicon rod is fixed distally to the remnant of the flexor tendon at the distal phalanx. The proximal end of the rod is left free (unsutured) in the distal forearm. Hence, the rod insertion is not expected to result in any active flexion of the finger. The author reports on a case series in which adhesions have occurred between the rod and the adjacent flexor tendons in the distal forearm. METHODS: A retrospective study of 110 patients who underwent 2-stage flexor tendon reconstruction by the author revealed 5 patients in which the fingers were actively moving good enough after the insertion of the silicone rod to the extent that patients refused to undergo the second grafting procedure. Complications, range of motion, strength, and patient satisfaction were documented. RESULTS: There were no complications related to the surgery or the presence of the rod for several years. Using the Strickland criteria, all patients qualified for a good outcome. Grip strength of the affected hand averaged 85% of the contralateral normal hand, and the pinch strength of the affected finger against the thumb averaged 68% compared with the contralateral side. All patients/parents were satisfied. Ultrasound imaging confirmed the presence of adhesions between the proximal end of the silicone rod and the adjacent flexor tendons. CONCLUSIONS: Our series documents a very unusual "desirable" event following the first-stage flexor tendon reconstruction. The study also documents the lack of silicone rod-related complications on long-term follow-up. The results may also encourage the use of permanent implants in flexor tendon reconstruction.

Inclusion of joint laxity, recurrent patellar dislocation, and short distal ulnae as a feature of Van Den Ende-Gupta syndrome: a case report.

BACKGROUND: Van Den Ende-Gupta Syndrome (VDEGS) is an extremely rare autosomal recessive syndrome with less than 20 reported families (approximately 40 patients) in the worldwide literature. CASE PRESENTATION: We have assessed one consanguineous Saudi family with typical features of VDEGS. Two siblings were affected with almost identical features; including blepharophimosis, arachnodactyly, flexion contractures of the elbows, camptodactyly, slender ribs, hooked lateral clavicular ends, and bilateral radial head dislocations. Both patients had several unusual features; including joint laxity, flat feet, recurrent patellar dislocations, and bilateral short distal ulnae. Full sequencing of SCARF2 revealed a homozygous mutation c.773G > A (p. Cys258Tyr) in both affected children. The parents (both with no abnormalities) were heterozygous for the same mutation. CONCLUSION: Joint laxity, recurrent patellar dislocations, and short distal ulnae should be included as part of the clinical spectrum of VDEGS.

Upper limb muscle overgrowth with hypoplasia of the index finger: a new over-growth syndrome caused by the somatic PIK3CA mutation c.3140A>G.

BACKGROUND: Scientists have previously described an overgrowth syndrome in Saudi patients and named it 'Upper limb muscle overgrowth with hypoplasia of the index finger' syndrome. CASE PRESENTATION: We describe a new case and document that the syndrome is caused by the somatic PIK3CA mutation c.3140A>G, p.His1047Arg. We also recruited one of the previously reported cases and found the same somatic mutation in the affected muscles. A wider classification of 'PIK3CA-related pathology spectrum' is presented which includes cancer, benign skin lesions/tumors, Cowden syndrome, isolated vascular malformations and various overgrowth syndromes. The latter entity is sub-divided into 3 sub-groups: overgrowth with brain involvement, overgrowth with multiple lipomatosis, and overgrowth without brain involvement/multiple lipomatosis. CONCLUSION: Our literature review indicated that "upper limb muscle overgrowth with hypoplasia of the index finger" is not as rare as previously thought to be. This overgrowth syndrome is unique and is caused by the somatic PIK3CA mutation c.3140A>G.

Expanding the allelic disorders linked to TCTN1 to include Varadi syndrome (Orofaciodigital syndrome type VI).

Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel-Gruber syndrome.

Management of Myositis Ossificans of the Hand: A Case Report and a Review of the Literature.

Myositis ossificans is a rare form of self-limiting heterotopic ossification of muscles. Most cases are seen in the thigh; the standard approach to these cases has been nonsurgical management awaiting spontaneous resolution. We report on a rare case of myositis ossificans of the hand with severe symptoms treated with early marginal excision without a trial of nonsurgical management.

Novel copy number variants and major limb reduction malformation: Report of three cases.

Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.

Conventional and Cellular Atypical Lipomas of the Hand and Forearm: A Report of 9 Cases.

PURPOSE: To report a case series of atypical lipomas of the hand and forearm and review the literature to define the clinical presentation, surgical approach, and postoperative complications including recurrence. METHODS: All cases of atypical lipomas of the hand and forearm treated by the author between 1994 and 2010 were retrospectively reviewed. The charts were reviewed for age, gender, tumor site, symptoms, preoperative studies, tumor size, type of surgical excision, and postoperative complications including recurrence. RESULTS: Nine cases were identified. All patients were middle-aged adults with a mean age of 55 years (range, 40-65 years). There were 5 women and 4 men. All patients presented with a single, painless, enlarging mass in either the palm or the volar forearm. Magnetic resonance imaging showed the tumors to be hyperintense on T1- and hypointense on T2-weighted images. All patients had marginal excision of the tumor. Histologically, 5 tumors were conventional, and 4 tumors were cellular atypical lipomas. The mean follow-up was 10 years (range, 6-16 years). There was no evidence of recurrence by clinical examination at final follow-up. CONCLUSIONS: The results of the current series and a review of the literature suggest that atypical lipomas of the hand and forearm may have a more benign behavior than atypical lipomas of other anatomical sites. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Defining the Indications of Pedicled Groin and Abdominal Flaps in Hand Reconstruction in the Current Microsurgery Era.

Three decades ago, pedicled flaps from the groin and abdomen were the workhorses in hand and forearm reconstruction. These pedicled flaps have several disadvantages including patient discomfort, stiffness, the need for flap division, and the inability to elevate the hand after acute trauma. Hence it is not surprising that free flap reconstruction has become the method of choice in coverage of complex hand and forearm defects. Despite this, pedicled flaps may still be indicated in the current era of microsurgery. Based on a review of the literature and the author's experience, the current review defines these indications as follows: complex defects in children aged less than 2 years; coverage of digital stump defects in preparation for toe-to-hand transfer; high-voltage electric burns with the hand surviving on collateral blood supply; salvage of the thumb ray in high-voltage electric burns with concurrent thrombosis of the radial artery; mutilating hand injuries; length preservation of multiple digital amputations in manual workers; and multiple defects within the digits, hand, or forearm. These indications are discussed along with clinical examples.

Six Cases of Myofibroma--The Adult Counterpart of Infantile Myofibromatosis: Case Report.

The adult counterpart of infantile myofibromatosis is rare and is known as myofibroma. Cases are rare, and previous ones have been reported as isolated case reports; hence, there has been no consensus regarding the clinical presentation, surgical reconstruction, histological features, and recurrence of hand myofibromas. Over a 10-year period, the senior author treated 6 patients. We review our cases as well as 6 previously reported cases. The presentation is usually a single hand mass in a young adult. The tumor may arise from the lower dermis or from deeper fibrous structures of the hand including the palmar fascia. Tumors that arise from the dermis are best treated by skin excision to ensure complete excision. Histologically, the tumor is composed of highly cellular myofibroblast proliferation and is strongly positive to smooth muscle actin immune stain. The recurrence rate after excision is low.

Two novel homozygous missense mutations in the GDF5 gene cause brachydactyly type C.

Mutations of the GDF5 gene cause a variable phenotype including brachydactyly type C. A review of the literature showed that it is caused either by heterozygous frameshift mutations within the prodomain or heterozygous missense/nonsense mutations within the active domain. Only a single patient with a homozygous mutation (c.517A > G, which predicts p. Met173Val) has been reported in this disorder. In this paper, we report two children with novel homozygous missense mutations in the GDF5 gene associated with brachydactyly type C: one mutation was within the region coding for the prodomain (c.608C > A, which predicts p.Thr203Asn) and the other was within the region coding for the active domain (c.1456 G > A, which predicts p.Val486Met). The genotype-phenotype correlations in the mutational spectrum of the GDF5 gene are discussed.

Conservative management of partial extensor tendon lacerations greater than half the width of the tendon in manual workers.

Conservative management (without suturing or splints) of partial extensor tendon lacerations greater than half the width of the tendon has not been previously investigated. In this prospective study, a total of 45 injured tendons (with lacerations involving 55%-90% of the width of the tendon) in 39 patients were treated conservatively. Injury zones I, III, and V of the fingers; and zones I and III of the thumb were excluded. Immediate non-resistive active mobilization was initiated and continued for 4 weeks, followed by resistive exercises. Patients were allowed to go back to work after 6 weeks. There were no cases of ruptures, triggering, infection, or complex regional pain syndrome. At final follow-up (8-9 months after injury), all patients obtained full range of motion with no extension lags. All patients were able to go back to normal duties. We conclude that early active motion without the use of splints or sutures in major extensor tendon lacerations in zones II, IV, VI-VIII of the fingers; and zones II, IV, and V of the thumb is safe.

External Rotation Osteotomy of the Humerus to Salvage the Failed Latissimus Dorsi Transfer in Children With Erb Birth Palsy and Supple Congruent Shoulders.

Management of the failed latissimus dorsi muscle transfer to restore shoulder external rotation has received little attention in the literature. We report on 6 children with Erb birth palsy and supple congruent shoulders and who underwent external rotation osteotomy to salvage a failed latissimus dorsi transfer. It is standard of care to do humerus osteotomies only to children with significant deformities of the glenohumeral joint. In the current article, the osteotomy was performed despite the presence of supple congruent shoulders because the osteotomy seemed the best and simplest option available. The functional outcome was satisfactory; with all patients reaching the occiput easily. Furthermore, there were improvement of the standing posture and improvement of the elbow flexion contracture. We conclude that the osteotomy procedure is a simple and effective option of management after a failed latissimus dorsi transfer.

Marked resorption of the thumb proximal phalanx following open reduction and K-wire fixation of a phalangeal neck fracture in a child: case report.

We report on a child with nonunion of a phalangeal neck fracture of the thumb following open reduction and K-wire fixation. There was progressive resorption of the proximal but not the distal fracture fragment. Successful reconstruction was obtained using a non-vascularized iliac crest bone graft.