A Case of Laurence Moon Bardet Biedl Syndrome.

INTRODUCTION: Laurence-Moon-Bardet-Biedl syndrome (LMBBS) is a rare autosomal recessive disorder characterised by polydactyly, retinitis pigmentosa, obesity, hypogonadism and mental retardation. MATERIALS: A 20-year old male, who is morbidly obese [BMI = 41] with history of intellectual delay, speech impairment and progressive vision loss. Presented to Saveetha medical college, Chennai with chief complaints of breathlessness, oliguria, abdominal distension. On examination patient had short stature, obese, crowded teeth present, had polydactyly of feet, micro penis and retinitis pigmentosa, nystagmus. He had pedal edema and facial puffiness. Laboratory investigations revealed Hb-6.9, creatinine-12, urea 217, potassium-7.7, bicarbonate-8.3. Echo showed eccentric Left ventricular hypertrophy. CT abdomen revealed hepatomegaly, right contracted kidney with renal pelvic lipomatosis, left enlarged kidney with hydroureteronephrosis grade 4. RESULT: He presented with all the primary Pentad features of LMBBS along with CKD stage 5. He also had secondary features like speech delay, developmental delay, dental crowding, high arched palate, left ventricular hypertrophy. CONCLUSION: LMBBS is a disorder with an identified Pentad of symptoms which are obesity, hypogonadism, intellectual impairment, polydactyly and retinitis pigmentosa. Renal function loss is most common cause of mortality in these patients. Because of seemingly unrelated symptoms the disorder remains largely under diagnosed. Genetic counselling of effected families raise awareness about need to get the other family members assessed for renal and cardiovascular problems. References Khan PA, Nishaat J, Noor S, et al. Laurence Moon Bardet Biedl syndrome: a rare case report in a tertiary care teaching hospital, Hyderabad, Telangana, India. Int J Med Sci Public Health 2017;7(1):68-71. Katsanis N, Lupski JR, Beales PL. Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 2001;10(20):2293-2299.

Holoprosencephaly in Patau Syndrome.

OBJECTIVE: To evaluate radiological (gestational and perinatal) and neonatal signs of patients with Patau syndrome and semilobar holoprosencephaly, as well as to report the association of both pathologies. CASE DESCRIPTION: This case report is about a female infant, born at term with trisomy of the chromosome 13 and semilobar holoprosencephaly, with thalamic fusion and a single cerebral ventricle, in addition to several other changes that worsened the patient's prognosis. COMMENTS: Chromosome 13 trisomy is a genetic alteration that leads to the symptoms that determines Patau syndrome. In this syndrome, cardiovascular, urogenital, central nervous system, facial structure and intellectual impairment are common, in addition to problems in limb formation, such as decreased humerus and femur length, polydactyly, hypotelorism and low ear implantation. It is estimated, however, that holoprosencephaly is present in only 24 to 45% of the patients with trisomy 13.

Bardet-Biedl syndrome associated with novel compound heterozygous variants in BBS12 gene.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by 6 primary features of rod-cone dystrophy, central obesity, polydactyly, cognitive impairment, hypogonadism and/or genitourinary malformations, and kidney abnormalities. At least 21 genes associated with BBS have been reported. To date, BBS associated with BBS12 variants has never been described in the Japanese population. We report a Japanese infant female with BBS with compound heterozygous BBS12 variants. METHODS: In addition to the pediatric examination, fundus photography, full-field electroretinogram(ffERG) and whole exome sequencing (WES) were underwent. RESULTS: The infant exhibited obesity, polydactyly, cognitive impairment, genitourinary malformations, and kidney dysfunction. At the age of 2 years, ffERG revealed severe reduction in both rod- and cone-mediated electroretinographic responses consistent with a severe form of rod-cone dystrophy, with minimal retinal abnormalities. WES revealed novel compound heterozygous BBS12 variants (c.591T > A, p.Tyr197* and c.1372dupA, p.Thr458Asnfs*5) in the infant. Her parents carried each of the variants, as confirmed by Sanger sequencing. CONCLUSIONS: The current observations will contribute to an expanded understanding of genotype-phenotype associations in BBS12-associated BBS.

A novel homozygous variant in the GLI1 underlies postaxial polydactyly in a large consanguineous family with intra familial variable phenotypes.

Polydactyly is a human inherited disorder caused by to anomalies in the genes involved in autopod development. The disorder segregates in both autosomal recessive and autosomal dominant form. Up till now, eleven genes causing non-syndromic polydactyly, have been identified. This includes ZNF141, GLI3, ZRS in LMBR1, MIPOL1, PITX1, IQCE, GLI1, FMA92A1, KIAA0825, STKLD1, and DACH1. In the present study, we have investigated a large consanguineous family of Pakistani origin segregating polydactyly in autosomal recessive pattern. Clinical examination of affected individuals revealed a non-syndromic form of the disorder. Genetic study based on homozygosity mapping and Sanger sequencing using DNA of the normal and affected individuals found a novel homozygous missense sequence variant [NM_005269.3: c.1133C > T, p.(Ser378Leu)] in the GLI1 located on human chromosome 12q13.3. In silico analysis of the identified variant showed a significant change in the secondary structure of the mutant protein that affects its function. Findings of the present study expand the mutation spectrum of the GLI1. In addition, the study will help in prevention of the disorder through carrier testing and bringing awareness among families affected with polydactyly.

Bardet-Biedl syndrome: a case series.

BACKGROUND: Bardet-Biedl syndrome is a rare multisystem autosomal recessive disorder that falls under the spectrum of ciliopathy disorders. It is characterized by rod-cone dystrophy, renal malformations, polydactyly, learning difficulties, central obesity, and hypogonadism. Many minor features that are related with Bardet-Biedl syndrome might aid in diagnosis and are crucial in clinical management. Bardet-Biedl syndrome is diagnosed on the basis of clinical signs and symptoms, which can be confirmed by genetic testing. Here we present four cases of Bardet-Biedl syndrome. To our knowledge, these are the first cases of Bardet-Biedl syndrome reported from Sudan. CASE PRESENTATION: Here, we report four Sudanese patients who presented with a variety of clinical manifestations of Bardet-Biedl syndrome (two males, 50 and 16 years old; two females, 38 and 18 years old). The first two patients presented with features of chronic kidney disease. The third patient had recently been diagnosed with type 1 diabetes and diabetic ketoacidosis. The fourth patient showed signs of retinal dystrophy early on. Case 1: a 38-year-old female presented with vomiting and irritability; the patient was diagnosed with Bardet-Biedl syndrome as she fulfilled six items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, renal abnormalities, learning disabilities, and genitourinary malformations), as well as one secondary feature (cardiovascular involvement, that is, left ventricular hypertrophy). Case 2: a 50-year-old male presented with fatigability; the patient was diagnosed with Bardet-Biedl syndrome as he fulfilled four items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, and renal abnormalities) in addition to two secondary features (diabetes mellitus and cardiovascular involvement, that is, left ventricular hypertrophy). Case 3: an 18-year-old female presented with polyuria, polydipsia, weight loss, and epigastric pain for 2 days; the patient was diagnosed with Bardet-Biedl syndrome because he had four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) in addition to three secondary features (developmental delay, diabetes mellitus, and strabismus). Case 4: a 16-year-old male presented with a blurring of vision; the patient was diagnosed with Bardet-Biedl syndrome as he exhibited four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) plus two secondary features (developmental delay and cataract). CONCLUSION: The scarcity of Bardet-Biedl syndrome necessitates a high index of suspicion to diagnose this syndrome. Increased awareness among physicians is required for the early diagnosis and treatment of Bardet-Biedl syndrome and to avoid complications and mortality.

Polymicrogyria, aventriculy, polydactyly, encephalocele, callosal agenesis (PAPEC): a new syndrome?

INTRODUCTION: Aventriculy is a very rare observation and is generally associated with holoprosencephaly. We report here a case of polymalformation affecting the brain, hands, and feet observed in a highly consanguineous family in Niger. CASE REPORT: A boy was born from a highly consanguineous family presenting multiple malformations (aventriculy, extreme microcephaly, polydactyly, polymicrogyria, callosal agenesis, and parietal encephalocele). To the best of our knowledge, such association has never been reported so far. DISCUSSION: We propose to name this association PAPEC (for polymicrogyria, aventriculy, polydactyly, encephalocele, and callosal agenesis). The occurrence of this disease in a highly consanguineous family suggests a genetic origin. Furthermore, we propose hypotheses that could explain pathophysiology of this defect.

De Novo GLI3 Pathogenic Variants May Cause Hypotonia and a Range of Brain Malformations Without Skeletal Abnormalities.

BACKGROUND: GLI3 encodes a zinc finger transcription factor that plays a role in the sonic hedgehog pathway. Germline pathogenic GLI3 variants are associated with Greig cephalopolysyndactyly and Pallister-Hall syndromes, two syndromes involving brain malformation and polydactyly. METHODS: We identified patients with pathogenic GLI3 variants and brain malformations in the absence of polydactyly or other skeletal malformation. RESULTS: Two patients were identified. Patient #1 is a 4-year-old boy with hypotonia and global developmental delay. Brain MRI showed a focal cortical dysplasia, but he had no history of seizures. Genetic testing identified a de novo likely pathogenic GLI3 variant: c.4453A>T, p.Asn1485Tyr. Patient #2 is a 4-year-old boy with hypotonia, macrocephaly, and global developmental delay. His brain MRI showed partial agenesis of the corpus callosum, dilatation of the right lateral ventricle, and absent hippocampal commissure. Genetic testing identified a de novo pathogenic GLI3 variant: c.4236_4237del, p.Gln1414AspfsTer21. Neither patient had polydactyly or any apparent skeletal abnormality. CONCLUSIONS: These patients widen the spectrum of clinical features that may be associated with GLI3 pathogenic variants to include hypotonia, focal cortical dysplasia, and other brain malformations, in the absence of apparent skeletal malformation. Further study is needed to determine if GLI3 pathogenic variants are a more common cause of focal cortical dysplasia or corpus callosum agenesis than presently recognized.

Excision of Rudimentary Preaxial Polydactyly of the Hand with Use of Electrocautery.

BACKGROUND: Suture ligation has been used widely for the treatment of rudimentary type extra digits, but several complications related to this treatment have been reported. The purpose of this study was to describe a new technique for excision of rudimentary preaxial polydactyly of the hand using electrocautery and assess its clinical outcomes. METHODS: The authors performed a retrospective study of 34 thumbs (32 patients) that had undergone excision of rudimentary preaxial polydactyly using electrocautery under local anesthesia. The mean follow-up period was 16.5 months. RESULTS: All children had full range of thumb motion without angular deformity at the most recent follow-up. There were no postoperative complications such as bleeding or infection. In 33 thumbs (97.1% of 34 thumbs), there were no signs of residual digit prominence. One thumb had a residual digit prominence at the extra digit removal site. In two thumbs, scar hypertrophy was evident at the operation site. All parents of the patients except two were very satisfied with this technique and the mean visual analog scale score for satisfaction was 9.5 ± 2.0 (range, 0-10). CONCLUSIONS: Excision of rudimentary preaxial polydactyly of the hand with the use of electrocautery could remove an extra digit completely in 97.1% of the cases. This technique would be a useful alternative to suture ligation, surgical clip application, or surgical excision for the treatment of rudimentary preaxial polydactyly of the hand.

INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder.

Oral-facial-digital syndromes (OFDSs) as a subgroup of ciliopathies are rare genetic disorders characterized by the association of abnormalities of the face, oral cavity, and extremities. OFDS XVII is a recently described subtype of OFDS that presents with developmental delay, facial dysmorphism, high palate, tongue nodules, brain malformations, cardiac anomaly, polydactyly, renal malformation, and various other findings. OFDS XVII is caused by biallelic variants in INTU gene and is inherited autosomal recessively. Intu is part of the CPLANE protein module that has an essential role in the ciliary transport system and function. INTU pathogenic variants have been reported in two patients with OFDS XVII, in two patients with short-rib thoracic dysplasia-20 with polydactyly (SRTD20), and one with nephronophthisis so far. We report the third family in the literature with OFDS XVII, with urogenital malformations as an additional finding.

Sturge-Weber syndrome coexisting with polydactyly: a case report.

BACKGROUND: Sturge-Weber syndrome (SWS) is a sporadic congenital disorder, characterized by unilateral facial nevus flammeus associated with ipsilateral glaucoma, choroidal angioma and leptomeningeal hemangiomas. SWS can comorbid with other disorders in some patients, however, there has been no prior described case of SWS and polydactyly occurring in the same patient. CASE PRESENTATION: A 15-year-old girl with diagnosis of SWS presented to our hospital. She had bilateral glaucoma and extensive port-wine stains distributing in bilateral faces, left neck and left upper limb. Meanwhile, the patient was noted to demonstrate the superfluous digit attaching on the left thumb and was diagnosed as polydactyly. Trabeculectomy, with intraoperative application of mitomycin C and postoperative subconjunctival injections of 5-fluorouracil, was successful in controlling the intraocular pressure in both eyes. CONCLUSIONS: We report a case with bilateral SWS coexisting with unilateral polydactyly, which, to our knowledge, has not been recognized previously and adds further evidence to the existing literature. In view of the rare concurrence of SWS and polydactyly, the etiology is unclear and further investigation is required to explore the underlying pathogenesis.

A case report of bilateral mirror feet with varus deformity.

OBJECTIVES: To describe a rare case of bilateral mirror feet with varus deformity and review of literature. METHODS: AP and oblique radiographs of both feet were taken. RESULTS: On radiographs, right foot showed eight toes and seven metatarsals while left foot showed eight toes and seven metatarsals, the three extra toes were present preaxially (on hallux side) in both feet, showing characteristics of postaxial toes termed as "mirror foot". Varus deformity was noted at the subtalar joint, otherwise tarsal bones appeared normal. No any syndromatic association was present. CONCLUSION: Mirror foot is a very rare congenital anomaly, we put forward this case for its rarity and unusual late presentation at the age of 22.

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.

Posterior vertebral column resection for rigid proximal thoracic kyphoscoliosis with broken growing rods in a patient with Desbuquois dysplasia.

STUDY DESIGN: Case report. OBJECTIVE: To describe the importance of preoperative halo-gravity traction and posterior vertebral column resection (PVCR) for severe proximal thoracic kyphoscoliosis associated with Desbuquois dysplasia, after breakage of a growing rod construct. Desbuquois dysplasia is a rare, autosomal recessive chondrodysplasia characterized by short stature, joint laxity, kyphoscoliosis, and characteristic facial dysmorphism. Our 8-year-old patient developed severe, progressive, infantile-onset kyphoscoliosis and had been initially treated with Vertical Expandable Prosthetic Titanium Rib (VEPTR) rods. She subsequently underwent growing rod placement, but the eventual rod fracture resulted in a severe angular kyphosis. METHODS: Clinical and radiographic case review. RESULTS: The broken implants were removed, and she was treated with 2.5 months of preoperative halo-gravity traction. She then underwent a T4 PVCR and C7-L4 instrumented posterior spinal fusion. The patient had an uneventful postoperative course without any neurologic problems. Two years postoperatively, correction was well maintained with appropriate alignment and balance without implant breakage. CONCLUSION: To our knowledge, this is the first report of treatment of spinal deformity associated with Desbuquois dysplasia. Our results suggest that preoperative halo-gravity traction and PVCR are safe and efficacious techniques for severe rigid kyphoscoliosis in the cervicothoracic region associated with broken growing rods in a patient with Desbuquois dysplasia. LEVEL OF EVIDENCE: Level IV.

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the GLI2 Gene

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

Robot-assisted repair of a urogenital sinus with an anorectal malformation in a patient with McKusick-Kaufman syndrome.

INTRODUCTION: A urogenital sinus (US) and an anorectal malformation (ARM) are a rare constellation of anomalies, and the optimal surgical approach is unclear. Open and laparoscopic approaches have been described for US and ARM, but no data exist to support robotic assistance in children. CASE: A 20-month-old Amish female presented to the study center with fever and abdominal pain. Abdominal ultrasound showed a large fluid-filled vagina, urinalysis was positive, and she was admitted for antibiotic therapy. Magnetic resonance imaging (MRI) confirmed hydrocolpos. An examination under anesthesia including cystoscopy demonstrated a short perineal body, an anteriorly displaced anus by muscle stimulation, and no vaginal opening. An ultrasound-guided, percutaneous vaginostomy tube was placed, and 650 cc of pus was drained. Vaginal and urine cultures grew similar strains of Escherichias coli. After a course of antibiotics, she underwent a robot-assisted mobilization of the intra-abdominal vagina and uterus, posterior sagittal anorectoplasty, vaginal pull-through, and a diverting colostomy. There were no intra-operative complications. Her Foley catheter was removed on post-operative day #3, and she voided spontaneously and was discharged in good condition. She remained in the hospital for ostomy teaching, but pain control and diet were not barriers to discharge after 12 h. CONCLUSION: Robotic mobilization of the intra-abdominal vagina in a pediatric patient with US and ARM is technically feasible and can be accomplished safely. Further comparative studies to other approaches are lacking. In this case, the robot allowed for good visualization, intra-operative collaboration between multiple specialties for complex patients with aberrant anatomy, and easy dissection in a narrow pre-pubertal pelvis and would be an approach that the study group uses in future cases.

A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly.

Mesoaxial synostotic syndactyly (MSSD) with phalangeal reduction is an uncommon congenital limb abnormality characterized by central osseous synostosis at a metacarpal level, mesoaxial reduction of the fingers, and preaxial cutaneous syndactyly in toes. In rare cases, the disease is also associated with fifth finger clinodactyly and postaxial polydactyly. It has autosomal recessive inheritance pattern caused by homozygous variants in the gene BHLHA9 mapped at chromosome 17p13.3. In the present study, a consanguineous family of Pakistani origin segregating MSSD in autosomal recessive form was characterized at clinical and genetic levels. Clinically, the diseased individuals have MSSD associated with clinodactyly and polydactyly. Homozygosity mapping followed by Sanger sequencing of BHLHA9 revealed a novel frameshift variant NM_001164405.1: c.409-409delC; p.(His137Thrfs*61) segregating with the disease phenotypes in the family. This is the second report providing evidence of association of polydactyly with MSSD caused by frameshift variant in the gene BHLHA9. The present molecular investigation will support genetic counselling of the local population carrying diseased variants.