Otopalatodigital Spectrum Disorders

Abstract

CLINICAL CHARACTERISTICS The otopalatodigital (OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type I (OPD1). Otopalatodigital syndrome type II (OPD2). Frontometaphyseal dysplasia (FMD). 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 FMD, females are less severely affected than related affected males. Males do not experience progression of 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. Prenatal lethality is most common in males with MNS. TODPD is a female limited condition, characterized by terminal skeletal dysplasia, pigmentary defects of the skin, and recurrent digital fibromata. DIAGNOSIS/TESTING The diagnosis is made by a combination of clinical examination, radiologic studies, family history consistent with X-linked inheritance, and molecular genetic testing. FLNA is the only gene in which pathogenic variants are known to cause the otopalatodigital spectrum disorders. Molecular genetic testing (sequence analysis) of FLNA detects pathogenic variants in individuals with OPD1, OPD2, FMD, MNS, and TODPD. MANAGEMENT Treatment of manifestations: Hearing aids for deafness. Cosmetic surgery may correct the fronto-orbital deformity; orthopedic surgery may correct scoliosis; continuous positive airway pressure (CPAP) and mandibular distraction can improve airway complications related to micrognathia. Surveillance: Monitor for hearing loss and orthopedic complications including scoliosis and craniosynostosis. Evaluation of relatives at risk: Consider molecular genetic testing for the family-specific pathogenic variant in at-risk relatives. GENETIC COUNSELING The OPD spectrum disorders are inherited in an X-linked manner. If a parent of a proband with OPD1, OPD2, or FMD 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. Males with OPD2 do not reproduce; males with OPD1 or FMD transmit the pathogenic variant to all of their daughters and none of their sons. 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variant in the family is known.