Diagnosis and management
Otopalatodigital spectrum disorders (OPDSD) constitute a group of rare, congenital, X-linked conditions caused by mutations in the filamin A (FLNA) gene. It includes four syndromes: OPSD type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia (FMD), and Melnick–Needles syndrome (MNS).
These disorders are distinguished by skeletal dysplasia of varying degrees affecting both the axial and appendicular skeletons, along with various extraskeletal defects. Its prenatal appearance is rather unspecific, hence diagnosis is usually made after birth.
Females are less severely affected by FMD1 than related affected males. Males do not suffer increasing skeletal dysplasia, but they may have joint contractures and abnormalities of the hand and foot. Both males and females are affected by progressive scoliosis.
MNS has a considerable phenotypic variety; some people are diagnosed in maturity, while others require respiratory support and have a shorter lifespan. All known cases of MNS in males result in perinatal death. Upper airway obstruction is frequently related to OPDSD.
Taybi reported oto-palato-digital syndrome in 1962, while Dudding et al. were the first to apply the term to the disease in 1967. Dudding et al. (1967) described three male siblings who had conduction deafness, cleft palate, distinctive facial features, and extensive bone abnormalities.
The patient has a pugilistic appearance due to a large nasal root. The wide spacing of the toes resembles the foot of a tree frog. Neither X-linkage nor autosomal inheritance could be differentiated. Langer examined the roentgenologic aspects of the same patients (1967).
These disorders are caused by mutations in the FLNA gene located on the X chromosome. The FLNA gene encodes filamin A, a cytoskeletal protein that binds actin via its N-terminal domain and other protein partners via its C-terminal domain. It is ubiquitously expressed in cells and is needed for membrane integrity as well as the coupling of signal transduction to actin cytoskeleton regulation. OPDSD-causing FLNA gene mutations are typically missense mutations or minor deletions that do not change the reading frame, resulting in a gain-of-functions mutation.
The FLNA gene codes for the protein filamin A, which aids in the formation of the network of protein filaments (cytoskeleton) that gives cells structure and allows them to alter shape and move.
Filamin A interacts with another protein called actin and assists it in the formation of the cytoskeleton's branching network of filaments. Filamin A also connects actin to a variety of other proteins, allowing them to carry out numerous roles within the cell.
Mutations related to OPD type I are predominantly found in the protein's CH2 domain and the location of the mutation is thought to determine disease severity. Mutations in the CH2 domain affect its activity and disrupt its interaction with F-actin, resulting in cytoskeleton instability and signal transduction disruption.
The FLNA gene mutations that cause OPDSD all produce alterations to the filamin A protein in the actin-binding region. The alterations are referred to as "gain-of-function" because they appear to result in a protein with a greater ability to bind to actin.
Researchers believe the mutations affect cytoskeleton integrity and disturb cellular processes involved in skeletal development, but it is unclear how changes in the protein connect to the specific signs and symptoms of the disorders.
Otopalatodigital syndrome type 1 (OPD1) is a developmental condition characterized mostly by skeletal abnormalities. It is typically the least severe of the otopalatodigital spectrum disorders.
This disorder is distinguished by distinctive facial traits such as wide-set and downward-slanting eyes, pronounced brow ridges, and a large, flat nose. Affected people exhibit finger and toe deformities such as flat, spatulate fingertips, shorter thumbs, and large toes.
Other characteristics include exceptionally lengthy second toes and a large gap between the first and second toes. Affected individuals also experience hearing loss.
Most indications of OPD1 are present before birth. Females with OPD 1 frequently have more variable signs and symptoms than males, while some have just modest indications. Otopalatodigital syndrome type 1 is a rare condition that affects less than one in every 100,000 people. Its precise occurrence is unclear.
In two successive pregnancies, Joksic et al. presented prenatal ultrasonography and postmortem evidence that led to the diagnosis of OPD type I. This is the first report of OPD type I prenatal diagnosis (PND).
Facial dysmorphy (hypertelorism, micrognathia, cleft palate) and digital defects were observed in affected fetuses, which are typical with OPD type I. Microphthalmia and early neonatal death due to severe respiratory distress syndrome are also described as novel features of the illness.
Clinical exome sequencing showed a pathogenic hemizygous missense variant in the FLNA gene. They believe that the existence of hypertelorism, micrognathia, and digital defects on prenatal ultrasound should raise the possibility of OPDSD.
OPD type 2 is characterized by anomalies in skeletal development, but it can also cause problems in other parts of the body, including the brain and heart. Growth and mental impairments, cerebellar hypoplasia, fixed overlapping fingers, hypertelorism, polydactyly, and conductive hearing loss are all symptoms of type II OPD.
Small mouth and jaw, cleft palate, flattened vertebrae, pectus, thin ribs, and adrenal hypoplasia are also frequent structural malformations. Individuals with OPD2 may suffer cognitive delays, hydrocephalus, omphalocele, and cardiac issues in addition to skeletal abnormalities. Chest anomalies, ureter blockage, and hypospadias in males can also be seen.
Females are less severely afflicted by OPD2 than comparable affected males. The majority of males with OPD2 die during their first year of life, mainly as a result of thoracic hypoplasia leading to pulmonary insufficiency. Males who survive the first year of birth are typically developmentally delayed and require respiratory care as well as feeding aid.
Diagnosis and management
Characteristic clinical and radiographic symptoms, along with a family history consistent with X-linked heredity, are used to make the diagnosis of an X-OPD spectrum disorder.
In males, molecular genetic testing can confirm the diagnosis by identifying a hemizygous pathogenic mutation in FLNA. In females, molecular genetic testing can confirm the diagnosis by identifying a heterozygous pathogenic mutation in FLNA.
The management of OPSDS requires a multidisciplinary approach. Hand and foot abnormalities may necessitate surgical intervention. Physiotherapy can help with contractures, and cosmetic surgery can help with fronto-orbital deformities.
Continuous positive airway pressure (CPAP) and mandibular distraction can help with micrognathia-related airway problems. Deafness can be treated with hearing aids.
- Joksic I, et al. (2016). Otopalatodigital Syndrome Type I: Novel Characteristics and Prenatal Manifestations in two Siblings. Balkan Journal of Medical Genetics, vol. 22,2 83-88. 21 Dec. doi:10.2478/bjmg-2019-0024. https://pubmed.ncbi.nlm.nih.gov/31942422/
- Moutton S, et al. (2016). Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. Journal of Human Genetics, vol. 61,8: 693-9. doi:10.1038/jhg.2016.37. https://www.nature.com/articles/jhg201637
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