A case report on fibular aplasia, tibial campomelia, oligosyndactyly syndrome variant in a male infant.

Fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO syndrome) is a rare, genetic, congenital limb malformation characterised by unilateral or bilateral fibular aplasia, tibial campomelia, and lower limb oligosyndactyly involving the lateral rays. A newborn male born at term via a Caesarean Section presented with malformations consisting of tibial campomelia, unilateral fibular hypoplasia, and oligosyndactyly, a "FATCO variant" case. On radiographic examination, an anterolateral shortened and bowed right lower limb at the distal third of the tibia, a rudimentary right fibula and absence of three rays on right foot were revealed. "FATCO syndrome" although rare may be linked to involvement of different body systems with morbidity and mortality. Proper parent counseling is a key aspect of this syndrome. Timely diagnosis and management with a multidisciplinary approach is essential to avoid lifelong disability, which can be a hurdle in a developing country.

Prenatal diagnosis of fibular aplasia-tibial campomelia-oligosyndactyly syndrome: Two case reports and review of the literature.

Fibular aplasia-tibial campomelia-oligosyndactyly also known as FATCO syndrome is a rare condition characterized by fibular aplasia, shortening and anterior bowing of the lower limb at the tibia with overlying soft tissue dimpling and oligosyndactyly. Its etiology is currently unknown, but there is a male predominance. There are less than 30 cases reported in the literature but only three with prenatal diagnosis. We report two cases of FATCO syndrome with prenatal lower limb malformation diagnosis. Identification of the ultrasound findings of this condition in the prenatal stages allows an adequate parental counselling regarding the clinical features, prognosis, and potential treatments.

Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management.

OBJECTIVE: The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar. METHOD: Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel. RESULTS: Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks. CONCLUSION: Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases.

When standard genetic testing does not solve the mystery: a rare case of preimplantation genetic diagnosis for campomelic dysplasia in the setting of parental mosaicism.

OBJECTIVE: To report a rare case of somatic mosaicism with a germline component of campomelic dysplasia in a woman undergoing in vitro fertilization with preimplantation genetic diagnosis (IVF-PGD). DESIGN: Case report. SETTING: Clinic. PATIENT(S): A 28-year old G2P0110 and her 34-year old husband had two previous pregnancies complicated by fetal campomelic dysplasia with suspected germline mosaic mutation. The couple, both phenotypically normal, underwent IVF-PGD to reduce their chances of transmission. None of the embryos could initially be determined to be disease free, because all embryos shared either a maternal or a paternal short tandem repeat haplotype with the products of conception from her last pregnancy. INTERVENTION(S): Peripheral-blood cytogenomic single-nucleotide polymorphism (SNP) microarray to identify the carrier of the mutation, and IVF-PGD to identify the disease-free embryo. MAIN OUTCOME MEASURE(S): Disease-free embryo. RESULT(S): Only one of the five euploid embryos was identified as disease free. CONCLUSION(S): A woman with suspected germline mosaicism for campomelic dysplasia was found to be a somatic mosaic with a germline component via a peripheral blood SNP microarray test. This identified her solitary disease-free embryo, which was transferred to her uterus but did not result in a viable pregnancy.

A novel association of campomelic dysplasia and hydrocephalus with an unbalanced chromosomal translocation upstream of SOX9.

Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in SOX9 or chromosomal rearrangements involving the long arm of Chromosome 17 harboring the SOX9 locus. SOX9, a transcription factor, is indispensible in establishing and maintaining neural stem cells in the central nervous system. We present a patient with angulation of long bones and external female genitalia on prenatal ultrasound who was subsequently found to harbor the chromosomal abnormality 46, XY, t(6;17) (p21.1;q24.3) on prenatal genetic testing. Comparative genomic hybridization revealed deletions at 6p21.1 and 17q24.3, the latter being 2.3 Mb upstream of SOX9 Whole-exome sequencing did not identify pathogenic variants in SOX9, suggesting that the 17q24.3 deletion represents a translocation breakpoint farther upstream of SOX9 than previously identified. At 2 mo of age the patient developed progressive communicating ventriculomegaly and thinning of the cortical mantle without clinical signs of increased intracranial pressure. This case suggests ventriculomegaly in some cases represents not a primary impairment of cerebrospinal fluid dynamics, but an epiphenomenon driven by a genetic dysregulation of neural progenitor cell fate.

Familial campomelic dysplasia due to maternal germinal mosaicism.

Campomelic dysplasia is an autosomal dominant skeletal dysplasia caused by heterozygous SOX9 mutations. Most patients are sporadic due to a de novo mutation. Familial campomelic dysplasia is very rare. We report on a familial campomelic dysplasia caused by maternal germinal mosaicism. Two siblings showed the classic campomelic dysplasia phenotype with a novel SOX9 mutation (NM_000346.3: c.441delC, p.(Asn147Lysfs*36)). Radiological examination of the mother showed mild skeletal changes. Then, her somatic mosaicism of the mutation was ascertained. This is the first report of molecularly confirmed maternal germinal mosaicism for a SOX9 mutation. We suggest that a meticulous clinical examination of the parents, even if they are superficially healthy, is needed to avoid overlooking germinal mosaicism of SOX9 mutations.

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.

Reporte de caso de síndrome FATCO: aplasia fibular, campomelia de tibia y oligosindactilia / A case report of a patient with FATCO syndrome: fibular aplasia, tibial campomelia and oligosyndactyly

El síndrome FATCO, por las siglas en inglés de aplasia fibular (Fibular Aplasia), campomelia de tibia (Tibial Campomelia) y oligosindactilia (Oligosyndactyly), es un conjunto de malformaciones óseas, en las que la alteración se centra en los huesos de la pierna. Es una entidad rara y hay pocos casos descritos en la Literatura internacional, y, hasta ahora, no se ha descrito ningún caso en Colombia. Presentamos aquí el caso de un recién nacido de sexo masculino con signos clínicos de manera prenatal y posnatal consistentes con síndrome FATCO sin otras malformaciones asociadas. Exponemos también una breve discusión sobre las diferentes malformaciones óseas y otros casos de FATCO en el mundo.

The FATCO syndrome, (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) are bone malformations with main alteration in lower limbs. It is a rare entity and there are few cases reported in international literature, and so far there are not published cases in Colombia. Here we present a case of a male newborn with prenatal and postnatal signs consistent with FATCO syndrome without other organs malformations, and there is a brief discussion about this syndrome and other different malformations associated with it.

[A case report of a patient with FATCO syndrome: fibular aplasia, tibial campomelia and oligosyndactyly]. / Reporte de caso de síndrome FATCO: aplasia fibular, campomelia de tibia y oligosindactilia.

The FATCO syndrome, (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) are bone malformations with main alteration in lower limbs. It is a rare entity and there are few cases reported in international literature, and so far there are not published cases in Colombia. Here we present a case of a male newborn with prenatal and postnatal signs consistent with FATCO syndrome without other organs malformations, and there is a brief discussion about this syndrome and other different malformations associated with it.

El síndrome FATCO, por las siglas en inglés de aplasia fibular (Fibular Aplasia), campomelia de tibia (Tibial Campomelia) y oligosindactilia (Oligosyndactyly), es un conjunto de malformaciones óseas, en las que la alteración se centra en los huesos de la pierna. Es una entidad rara y hay pocos casos descritos en la Literatura internacional, y, hasta ahora, no se ha descrito ningún caso en Colombia. Presentamos aquí el caso de un recién nacido de sexo masculino con signos clínicos de manera prenatal y posnatal consistentes con síndrome FATCO sin otras malformaciones asociadas. Exponemos también una breve discusión sobre las diferentes malformaciones óseas y otros casos de FATCO en el mundo.

Skeletal dysplasia with bowing long bones: Proposed flowchart for prenatal diagnosis with case demonstration.

OBJECTIVE: Skeletal dysplasia with bowing long bones is a rare group of multiple characterized congenital anomalies. MATERIALS AND METHODS: We introduce a simple, practical diagnostic flowchart that may be helpful in identifying the appropriate pathway of obstetrical management. RESULTS: Herein, we describe four fetal cases of bent bony dysplasia that focus on ultrasound findings, phenotype, molecular tests, distinctive X-ray features, and chondral growth plate histology. The first case was a typical campomelic dysplasia resulting from a de novo mutation in the SOX9 gene. The second fetus was affected by osteogenesis imperfecta Type II carrying a mutation in the COLA1 gene. The third case was a rare presentation of campomelic dysplasia, Cumming type, in which SOX9 examination was normal. Subsequently, a femoral hypoplasia unusual facies syndrome is also discussed. CONCLUSION: Targeted molecular tests and genetic counseling are required for supplementing ultrasound imaging in order to diagnose the correct skeletal disorders.

Clinical, genetics and bioinformatics characterization of a campomelic dysplasia case report.

Campomelic dysplasia is a rare disorder characterized by skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or may develop as phenotypic females. This syndrome is caused by alterations in SRY-related HMG-Box Gene 9 (SOX9), a transcription factor essential in both chondrocyte differentiation and sex determination. We report a 27-week fetus with ambiguous genitalia and upper and lower extremities bone malformations. Gross photographs, radiologic and pathological studies led the clinical diagnosis to campomelic dysplasia. A new frameshift mutation (p.Pro415Serfs*163) was identified in the SOX9 gene by genetic analysis. This mutation not only alters almost the entire sequence of the C-terminal transactivation (TA) domain of SOX9, but also enlarges it. This altered sequence does not resemble any other existing sequence. Since TA domain is entirely affected, SOX9 could not establish its normal function. The comparison between p.Pro415Serfs*163 and other frameshift mutations that enlarges SOX9 showed the same nucleotides added. This new sequence is not conserved either. We speculate that the fact of adding a sequence downstream of the C-terminal domain alters SOX9 and leads to campomelic dysplasia. The clinical information is essential not only to achieve a correct diagnosis in fetuses with pathologic ultrasound findings, but also to offer a proper genetic counseling.

Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ∼1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16.

BACKGROUND: Campomelic dysplasia and acampomelic campomelic dysplasia (ACD) are allelic disorders due to heterozygous mutations in or around SOX9. Translocations and deletions involving the SOX9 5' regulatory region are rare causes of these disorders, as well as Pierre Robin sequence (PRS) and 46,XY gonadal dysgenesis. Genotype-phenotype correlations are not straightforward due to the complex epigenetic regulation of SOX9 expression during development. METHODS: We report a three-generation pedigree with a novel ∼1 Mb deletion upstream of SOX9 and including KCNJ2 and KCNJ16, and ascertained for dominant transmission of PRS. RESULTS: Further characterization of the family identified subtle appendicular anomalies and a variable constellation of axial skeletal features evocative of ACD in several members. Affected males showed learning disability. CONCLUSION: The identified deletion was smaller than all other chromosome rearrangements associated with ACD. Comparison with other reported translocations and deletions involving this region allowed further refining of genotype-phenotype correlations and an update of the smallest regions of overlap associated with the different phenotypes. Intrafamilial variability in this pedigree suggests a phenotypic continuity between ACD and PRS in patients carrying mutations in the SOX9 5' regulatory region.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

Campomelic dysplasia.

Campomelic dysplasia is a rare hereditary congenital osteochondral dysplasia characterized by abnormal bowing of the lower limbs, sex reversal in males, and other skeletal and extraskeletal abnormalities. It is usually fatal in the neonatal period because of respiratory insufficiency. The diagnosis is usually difficult because of its rare presentation and the prognosis is poor. We present such a case in a 1-month-old child with typical skeletal abnormalities, whose presentation was unusual because of later presentation of respiratory distress and lack of genitourinary abnormalities.

Congenital heart defects in patients with deletions upstream of SOX9.

Heterozygous loss-of-function coding-sequence mutations of the transcription factor SOX9 cause campomelic dysplasia, a rare skeletal dysplasia with congenital bowing of long bones (campomelia), hypoplastic scapulae, a missing pair of ribs, pelvic, and vertebral malformations, clubbed feet, Pierre Robin sequence (PRS), facial dysmorphia, and disorders of sex development. We report here two unrelated families that include patients with isolated PRS, isolated congenital heart defect (CHD), or both anomalies. Patients from both families carried a very similar ∼1 Mb deletion upstream of SOX9. Analysis of ChIP-Seq from mouse cardiac tissue for H3K27ac, a marker of active regulatory elements, led us to identify several putative cardiac enhancers within the deleted region. One of these elements is known to interact with Nkx2.5 and Gata4, two transcription factors responsible for CHDs. Altogether, these data suggest that disruption of cardiac enhancers located upstream of SOX9 may be responsible for CHDs in humans.