Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance

Abstract

Turner syndrome is a sex chromosome abnormality in which a female has a single X chromosome or structurally deficient second sex chromosome. The phenotypic spectrum is broad, and atypical features prompt discussion of whether the known features of Turner syndrome should be further expanded. With the advent of clinical whole exome sequencing, there has been increased realization that some patients with genetic disorders carry a second genetic disorder, leading us to hypothesize that a “dual diagnosis” may be more common than suspected for Turner syndrome. We report five new patients with Turner syndrome and a co-occurring genetic disorder including one patient with Li-Fraumeni syndrome, Li-Fraumeni and Noonan syndrome, mosaic trisomy 8, pathogenic variant in RERE, and blepharophimosis-ptosis-epicanthanus inversus syndrome. We also undertook an extensive literature review of 147 reports of patients with Turner syndrome and a second genetic condition. A total of 47 patients (31%) had trisomy 21, followed by 36 patients (24%) had one of 11 X-linked disorders. Notably, 80% of the 147 reported patients with a dual diagnosis had mosaicism for Turner syndrome, approximately twice the frequency in the general Turner syndrome population. This article demonstrates the potential for co-occurring syndromes in patients with Turner syndrome, prompting us to recommend a search for an additional genetic disorder in Turner patients with unusual features. Knowledge of the second condition may lead to modification of treatment and/or surveillance. We anticipate that increased awareness and improved diagnostic technologies will lead to the identification of more cases of Turner syndrome with a co-occurring genetic syndrome.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years

“…In addition to associated eye problems that are thought to be directly due to Turner syndrome, women may have a co‐occurring diagnosis, especially X‐linked ocular disorders which manifest in women with Turner syndrome because of the single sex chromosome. Most commonly reported is X‐linked red‐green color blindness, as well as X‐linked retinitis pigmentosum (Jones et al, ; Zhou et al, ), X‐linked juvenile retinoschisis (Jones et al, ) and X‐linked congenital nystagmus. Dual diagnoses with eye problems have included Mendelian syndromes such as blepharophimosis‐ptosis‐epicanthus inversus syndrome (BPES) and Axenfeld‐Reiger syndrome, and a mitochondrial disorder Leber hereditary optic neuropathy (Jones et al, ).…”

“…Most commonly reported is X‐linked red‐green color blindness, as well as X‐linked retinitis pigmentosum (Jones et al, ; Zhou et al, ), X‐linked juvenile retinoschisis (Jones et al, ) and X‐linked congenital nystagmus. Dual diagnoses with eye problems have included Mendelian syndromes such as blepharophimosis‐ptosis‐epicanthus inversus syndrome (BPES) and Axenfeld‐Reiger syndrome, and a mitochondrial disorder Leber hereditary optic neuropathy (Jones et al, ). Growing awareness is essential in order to correctly diagnosis eye problems as more than “just Turner syndrome”.…”

“…There is no conclusive proof that the absence or structural deficiency of the X chromosome in Turner syndrome causes cancer. Although case reports (including Alexiou et al, ; Hanaei, Habibi, Nejat, Sayarifard, & Vasei, ; Jones et al, ; Pier et al, ), case series (Larizza et al, ), and epidemiologic studies (Ji et al, ) provide support for an increase in certain types of cancer occurrence (showing a difference in pattern ), the overall risk does not appear to be increased (see also Section 4.2). Thus, surveillance for cancer is not indicated.…”

Case report: acromegaly and breast cancer in a woman with turner syndrome

“…Use of clinical whole-exome sequencing, has shown that, some patients with genetic disorders carry a second genetic disorder and dual diagnosis may be more common than suspected of the TS [2]. Of the investigated cases with TS, 80% had mosaicism for TS and dual diagnosis, approximately twice the frequency than in the general TS population [2].…”

Dual molecular diagnoses in a neurometabolic specialty clinic

“…Dual molecular diagnoses involve the distinct or overlapping clinical diagnosis of more than one genetic locus that segregates independently. There are numerous case reports in the literature of patients with co‐occurring genetic disorders (Balci, Hartley, Xi, et al, 2017; Bartoletti‐Stella et al, 2015; Brimble, Pacione, Farrelly, Stevenson, & Ruzhnikov, 2018; Donkervoort et al, 2013; Finsterer, 2020; Finsterer & Zarrouk‐Mahjoub, 2016; Hodapp et al, 2006; Jones, McNamara, Longoni, et al, 2018; Katiyar, Davies, & Goel, 2020; Martin et al, 2014; Masciullo et al, 2013; Murakami, Kimura, Enomoto, et al, 2019; Polavarapu et al, 2019; Posey et al, 2016; Retterer et al, 2016; Ricci et al, 2012; Scarlato et al, 2015; Schreiber et al, 2013; Smith et al, 2019; Splinter et al, 2018; Trujillano et al, 2017; Vona et al, 2018). Complete diagnosis of these cases can pose a challenge as it can be difficult to ascertain if an atypical clinical feature could represent a novel phenotype of the primary condition or are due to a second genetic or acquired disease.…”