What Does Orocraniodigital Syndrome Entail?
What does Orocraniodigital Syndrome entail? Orocraniodigital syndrome (OS), alternatively referred to as Juberg-Hayward syndrome, is a seldom-seen autosomal recessive disorder.
It is characterized by numerous abnormalities affecting the head, facial area (craniofacial), fingers, and toes. OS is a syndrome characterized by multiple malformations, including microcephaly, facial deformities, urogenital anomalies, intellectual disability, and various skeletal abnormalities. Some individuals have also been found to have microcephaly.
History
In 1969, Juberg and Hayward identified a condition characterized by oral, cranial, and digital manifestations in five out of six infant siblings.
The two brothers exhibited cleft lip and palate, microcephaly, hypoplasia, and distal placement of their thumbs, along with limitations in elbow extension. Among the four sisters, three had toe abnormalities, and both sisters and one brother had microcephaly, stiff thumbs, and a forme fruste cleft lip.
In 1982, Kingston et al. reported a single case involving a 17-year-old individual with unilateral cleft lip and palate, bilateral absent thumbs, aberrant carpal bones, radial head malformation, small stature (143.3 cm), and a growth hormone deficiency. X-rays revealed a normal sella turcica.
Nevin et al. (1981) described a female case with small stature attributed to the absence of the pituitary fossa, although no obvious endocrine abnormalities were detected. Verloes et al. (1992) documented three nonfamilial cases of orocraniodigital syndrome.
New features discovered by Verloes et al. (1992) included mental retardation (unrelated to the severity of the abnormalities), anterior anal displacement, and ptosis.
Verloes et al. (1992) suggested that recessive inheritance was likely, but autosomal dominant inheritance could not be entirely ruled out. Therefore, caution should be exercised in genetic counseling for parents of affected children and the affected individuals themselves.
Causes and Symptoms
In 2021, Kantaputra et al. made the first genetic discovery regarding the cause of this syndrome. According to their findings, OS is a result of a novel homozygous base substitution in the ESCO2 gene, leading to a nonsense mutation.
The majority of patients (>80%) display symptoms including intrauterine growth retardation, severe short stature, microcephaly, cleft lip or palate, and a broad nose. Additionally, 30-75% of patients may present with symptoms such as abnormal vertebral morphology, horseshoe kidney, hypertelorism, hammertoe, hypospadias, oral cleft, scoliosis, and abnormalities in elbows, ribs, and wrists. Other potential symptoms include radioulnar synostosis, toe syndactyly, and intellectual disability. Fewer than 30% of patients may experience anteriorly placed anus, dandy-Walker malformation, limited bone extension, abnormal abdominal morphology, toe abnormalities, and ptosis.
ESCO2 Gene
ESCO2 is a protein consisting of 601 amino acids with two conserved segments, a Zn finger-like motif, and a C-terminal acetyltransferase domain. It belongs to the Eco1 family of acetyltransferases.
This protein plays a role in the establishment of sister chromatid cohesion during the S phase and its maintenance until their separation in anaphase. It is also involved in post-replicative sister chromatid cohesion, which is initiated by double-strand breaks.
Patients with ESCO2 mutations typically exhibit a characteristic lack of cohesion in heterochromatic regions around centromeres and in the long arm of the Y chromosomes.
Epidemiology
The prevalence of OS is less than 1 in 1,000,000, with very few reported cases in the medical literature.
Case Report In 2021, Kantaputra et al. reported on a 2-year-old Lisu Thai girl with proportionally small stature, microcephaly, ptosis, a hanging nasal columella, and previously corrected cleft lip and palate. Her fingers were small, with particularly short second and fifth fingers, and clinodactyly in the fifth finger.
She also exhibited cutaneous syndactyly between fingers 2-3 and 4-5 on both hands. Limited elbow joint mobility had been present since birth, severely affecting pronation and supination. The X-rays showed shortened thumb and finger bones. Additionally, the carpal bones showed delayed bone age.
Orocraniodigital and Roberts syndromes share features including microcephaly, cleft lip/palate, ptosis, limb/digit anomalies, and autosomal recessive inheritance.
Roberts and Orocraniodigital syndromes link to ESCO2 gene homozygous mutations, causing acetyltransferase activity loss. Recent findings link Orocraniodigital Syndrome to ESCO2 gene homozygous mutation, hinting at an allelic connection with Roberts syndrome.
Diagnosis and Treatment
Orocraniodigital Syndrome is typically diagnosed shortly after birth (neonatal period) through a comprehensive clinical evaluation. The specific treatment approach depends on the severity and characteristics of each individual case.
Some craniofacial abnormalities associated with the syndrome may be corrected through surgical procedures. For example, infants with cleft lip may require surgical intervention, and in some cases, additional surgeries may be needed as the child grows.
Cleft palates can also be surgically corrected when necessary. Surgical correction of hand and/or foot abnormalities related to OS is possible in certain cases.
Genetic counseling can be valuable for affected individuals and their families. A multidisciplinary approach that includes social, educational, and medical support may benefit babies and children with this condition. Symptomatic and supportive treatments are often required.
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