Clinical diagnosis A clinical diagnosis of<unk>  is made in individuals with characteristic prenatal growth retardation, limb malformations, and craniofacial abnormalities. The specific characteristics that are looked for in the clinical diagnosis are listed below. * Prenatal growth retardation- low birth length and weight that can range from mild to severe * Limb malformations- bilateral symmetric tetraphocomelia, oligodactyly, thumb aplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures * Craniofacial abnormalities- bilateral cleft lip and palate, micrognathia, hypertelorism, exophthalmos, down-slanting palpebral fissures, malar hypoplasia, hypoplastic nasal alae, and ear malformations An official diagnosis of<unk>  relies on cytogenetic testing of the peripheral blood. Testing Cytogenetic testing Cytogenetic preparations that have been stained by either Giemsa or C-banding techniques will show two characteristic chromosomal abnormalities. The first chromosomal abnormality is called premature centromere separation (PCS) and is the most likely pathogenic mechanism for<unk> . Chromosomes that have PCS will have their centromeres separate during metaphase rather than anaphase (one phase earlier than normal chromosomes). The second chromosomal abnormality is called heterochromatin repulsion (HR). Chromosomes that have HR experience separation of the heterochromatic regions during metaphase. Chromosomes with these two abnormalities will display a "railroad track" appearance because of the absence of primary constriction and repulsion at the heterochromatic regions. The heterochromatic regions are the areas near the centromeres and nucleolar organizers. Carrier status cannot be determined by cytogenetic testing. Other common findings of cytogenetic testing on<unk>  patients are listed below. * Aneuploidy- the occurrence of one or more extra or missing chromosomes * Micronucleation- nucleus is smaller than normal * Multilobulated nuclei- the nucleus has more than one lobe Genetic testing At this point in time, ESCO2 is the only known gene to cause<unk>  mutations. Also, all individuals that have been diagnosed with<unk>  by cytogenetic techniques have also had ESCO2 mutations. Confirmation of a<unk>  diagnosis requires detection of the characteristic chromosomal abnormalities (PCS and HR) or the identification of two ESCO2 mutations that have been linked to<unk> . Carrier testing and prenatal diagnosis Carrier testing for<unk>  requires prior identification of the disease-causing mutation in the family. Carriers for the disorder are heterozygotes due to the autosomal recessive nature of the disease. Carriers are also not at risk for contracting<unk>  themselves. A prenatal diagnosis of<unk>  requires an ultrasound examination paired with cytogenetic testing or prior identification of the disease-causing ESCO2 mutations in the family. Genetically related disorders At this time, there are no other phenotypes (observable expressions of a gene) that have been discovered for mutations in the ESCO2 gene. Differential diagnosis In cases of mild malformations, the following disorders should be considered in the differential diagnosis: * Baller-Gerold Syndrome * Fanconi Anemia (FA) In cases of severe manifestations, the following disorders should be considered in the differential diagnosis: * Thrombocytopenia-Absent Radius (TAR) Syndrome * Tetra-Amelia, X-linked * Tetra-Amelia, Autosomal Recessive * Splenogonadal Fusion with Limb Defects and Micrognathia * DK Phocomelia Syndrome * Holt-Oram Syndrome * Thalidomide Embryopathy In cases of similar cytogenetic findings, the following disorders should be considered in the differential diagnosis: * Cornelia de Lange Syndrome (CdLS) * Mosaic Variegated Aneuploidy Syndrome Clinical description Little is known about the natural history of<unk>  due to its wide clinical variability. The prognosis of the disease depends on the malformations, as the severity of the malformations correlates with survival. The cause of death for most fatalities of<unk>  have not been reported; however, five deaths were reportedly due to infection. The following are observations that have been made in individuals with cytogenetic findings of PCS/HR or ESCO2 mutations: * The symptom of prenatal growth retardation is the most common finding and can be moderate to severe. Postnatal growth retardation can also be moderate to severe and correlates with the degree of severity of limb and craniofacial malformations. * In limb malformations, the upper limbs are typically more severely affected than the lower limbs. There have been many cases of only upper limb malformation. * In hand malformations, the thumb is most often affected, followed by the fifth finger (the little finger). In severe cases, the patient may only have three fingers and in rare cases only one. * In craniofacial malformations, mildly affected individuals will have no abnormalities of the palate. The most severely affected will have a fronto-ethmoid-nasal-maxillary encephalocele. * The severity of limb malformations and craniofacial malformations is correlated. * Other abnormalities can occur in different parts of the body, including: * Heart- atrial septal defects, ventricular septal defects, patent ductus arteriosus * Kidneys- polycystic kidney, horseshoe kidney * Male genitals- enlarged penis, cryptorchidism * Female genitals- enlarged clitoris * Hair- sparse, silvery-blonde scalp hair * Cranial nerve paralysis, moyamoya disease, stroke, intellectual disability
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