Clinical characteristics: The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following:
Otopalatodigital syndrome type 1 (OPD1)
Otopalatodigital syndrome type 2 (OPD2)
Frontometaphyseal dysplasia type 1 (FMD1)
Melnick-Needles syndrome (MNS)
Terminal osseous dysplasia with pigmentary skin defects (TODPD)
In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Diagnosis/testing: The diagnosis of an X-OPD spectrum disorder is established in a male proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive.
The diagnosis of an X-OPD spectrum disorder is usually established in a female proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive.
Management: Treatment of manifestations: Surgical treatment may be required for hand and foot malformations. Monitoring and surgical intervention as needed for scoliosis; physiotherapy for contractures; cosmetic surgery may correct the fronto-orbital deformity; continuous positive airway pressure (CPAP) and mandibular distraction can improve airway complications related to micrognathia; hearing aids for deafness; evaluation with anesthesiology if intubation and ventilation are required due to laryngeal stenosis.
Surveillance: Annual clinical evaluation for orthopedic complications including contractures and scoliosis; monitor head size and shape with each clinical evaluation in infancy for craniosynostosis; annual clinical evaluation for apnea with somnography studies as indicated; annual audiology evaluation.
Evaluation of relatives at risk: Consider molecular genetic testing for the family-specific pathogenic variant in at-risk relatives.
Genetic counseling: The X-OPD spectrum disorders are by definition inherited in an X-linked manner. If a parent of a proband with OPD1, OPD2, or FMD1 has the FLNA pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%.
When the mother has an FLNA pathogenic variant, males who inherit the variant will be affected; females who inherit the variant have a range of phenotypic expression. If the mother of a proband with TODPD or MNS has the FLNA pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the variant will be affected and usually exhibit embryonic lethality or die perinatally (MNS); females who inherit the variant have a range of phenotypic expression.
Males with OPD2 do not reproduce; males with OPD1 or FMD1 transmit the pathogenic variant to all of their daughters and none of their sons.
Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in the family is known.
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