What is Orocraniodigital Syndrome?

Orocraniodigital syndrome (OS), also known as Juberg-Hayward syndrome is a rare autosomal recessive condition.

Multiple abnormalities of the head and face (craniofacial area), as well as the fingers and toes, characterize it. OS is a polymalformative syndrome that includes microcephaly, facial dysmorphism, urogenital anomalies, and intellectual deficiency in addition to various skeletal anomalies. Some patients have been diagnosed with microcephaly.

History

In 1969, Juberg and Hayward identified a condition that manifested itself orally, cranially, and digitally in five of six siblings infants.

Cleft lip and palate, microcephaly, hypoplasia and distal placement of the thumbs, and elbow abnormalities limiting extension were all present in the two brothers. Three of the four sisters, as well as one of the brothers, had toe abnormalities. Microcephaly, stiff thumbs, and a forme fruste cleft lip were found among the sisters.

Kingston et al. described a single instance in 1982. A 17-year-old had bilateral nonexistent thumbs, aberrant carpal bones, radial head malformation, and small stature, in addition to unilateral cleft lip and palate (143.3 cm). He was discovered to be deficient in growth hormone. By X-ray, the sella turcica was normal.

Nevin et al. (1981) described a case of a female with small stature due to the lack of the pituitary fossa but no obvious endocrine abnormalities. Three nonfamilial examples of orocraniodigital syndrome were described by Verloes et al. (1992).

Mental retardation (unrelated to the severity of the abnormalities), anterior anal displacement, and ptosis were all new traits discovered by Verloes et al. (1992).

According to Verloes et al. (1992), recessive inheritance was likely, but the autosomal dominant inheritance could not be completely ruled out, therefore caution should be exercised in genetic counseling of parents of afflicted children and affected patients themselves.

Causes and symptoms

In 2021, Kantaputra et al. reported the genetic cause behind this syndrome for the first time. According to their report, OS is caused by a new homozygous base substitution in the establishment of the cohesion 1 homolog 2 (ESCO2) gene, which results in a nonsense mutation.

In the majority (>80%) of patients, intrauterine growth retardation, severe short stature, microcephaly, cleft lip or palate, and wide nose are observed. Around 30-75% of patients exhibit symptoms such as abnormal vertebral morphology, horseshoe kidney, hypertelorism, hammertoe, hypospadias, oral cleft, scoliosis, and abnormality of elbows, ribs, and wrist. Other symptoms that may also be present include radioulnar synostosis, toe syndactyly, and intellectual disability. Less than 30% of patients experience anteriorly placed anus, dandy-Walker malformation, limited bone extension, abnormal abdomen morphology, abnormality of the toe, and ptosis.

ECOS2 gene

ESCO2 is a 601-amino-acid acetyltransferase that has two conserved sections, a Zn finger-like motif, and a C-terminal acetyltransferase domain. It belongs to the Eco1 family of acetyltransferases.

This protein is involved in the formation of sister chromatid cohesion throughout the S phase and until their separation during anaphase. It is also involved in post-replicative sister chromatid cohesion, which is triggered by double-strand breaks.

The heterochromatic areas around centromeres and in the long arm of the Y chromosomes in patients with ESCO2 mutations display a typical lack of cohesion.

Epidemiology

The prevalence of OS is <1/1,000,000. Very few cases have been reported in the medical literature.

Case report

In 2021, Kantaputra et al. described a 2-year-old Lisu Thai girl with proportionately small stature, microcephaly, ptosis, a hanging nasal columella, and corrected cleft lip and palate. Her fingers were small, with the second and fifth fingers being especially short, and she had clinodactyly in the fifth finger.

She also exhibited cutaneous syndactyly between fingers 2-3 and 4-5 on both sides. Elbow joint movement had been restricted since birth, with pronation and supination severely reduced. Shortening of the metacarpals and phalanges of the thumbs, as well as the proximal and middle phalanges of the second and fifth fingers, was discovered on radiographic evaluation. Furthermore, the carpal bones had a late bone age.

Orocraniodigital syndrome and Roberts syndrome

Microcephaly, cleft lip and palate, ptosis, upper limb and digit anomalies, and autosomal recessive inheritance are all hallmarks of both orocraniodigital syndrome and Roberts syndrome.

Homozygous mutations in ESCO2, which cause acetyltransferase activity to be lost, have been shown to have a role in the pathophysiology of Roberts syndrome. OS was recently discovered to be caused by a homozygous mutation in the ESCO2 gene, implying that it is allelic with Roberts syndrome.

Diagnosis and treatment

Based on a thorough clinical evaluation, Orocraniodigital Syndrome is usually diagnosed immediately after delivery (neonatal period). The intensity and characteristics of each instance determine how this disease is treated.

Some of the craniofacial abnormalities associated with this condition may be corrected with surgery. Cleft lip in infants, for example, may necessitate surgery; in some situations, additional surgery may be required as the child gets older.

Cleft palates can also be corrected surgically. Surgical correction of hand and/or foot abnormalities related to OS is possible in some circumstances.

Affected individuals and their families will benefit from genetic counseling. For babies and children with this disease, a multidisciplinary approach that includes social, educational, and medical assistance may be beneficial. Symptomatic and supportive treatment is necessary.

References

• Juberg-Hayward syndrome. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/3060/juberg-hayward-syndrome
• JUBERG-HAYWARD SYNDROME; JHS. [Online] OMIM. Available at: https://www.omim.org/entry/216100
• Orocraniodigital Syndrome. [Online] National Organization for rare disorders. Available at: https://rarediseases.org/rare-diseases/orocraniodigital-syndrome
• Juberg-Hayward syndrome. [Online] Orphanet. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2175&Disease_Disease_Search_diseaseType=ORPHA&Disease_Disease_Search_diseaseGroup=2319&Disease(s)/group%20of%20diseases=Orocraniodigital-syndrome&title=Orocraniodigital-syndrome&search=Disease_Search_Simp
• Berger M, Rost I, & Schmidt H (2011). A novel chromosomal aberration in a child with suspected Juberg-Hayward syndrome. Clinical Dysmorphology, 20(2), 121–126. doi:10.1097/MCD.0b013e328341679e
• Kantaputra PN, Dejkhamron P, Tongsima S, et al. (2020). Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2. Archives of Oral Biology, 119, 104918. doi:10.1016/j.archoralbio.2020.104918
• Kantaputra PN, Dejkhamron P, Intachai W, et al. (2021). Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2. European Journal of Orthodontics, 43(1), 45–50. doi:10.1093/ejo/cjaa023

Further Reading

• All Genetic Disorder Content
• What are Genetic Disorders?
• Genetic Disorder Comorbidities
• Multifactorial And Polygenic (Complex) Genetic Disorder
• Single Gene Genetic Disorder