22 May 2023: Articles
Mother and Daughter with Short Stature, Microcephaly, Mild Dysmorphic Features, and Learning Disabilities Due to Ververi-Brady Syndrome Associated with a New Variant of the Gene
Diagnostic / therapeutic accidents, Rare disease, Educational Purpose (only if useful for a systematic review or synthesis)Marija Roddate1ABCDEF*, Gita Tauriņa2BCDE, Vladimirs Krutovs3EF, Dmitrijs Rots4CD, Viktorija Kēniņa45ABCD
Am J Case Rep 2023; 24:e939217
BACKGROUND: Ververi-Brady syndrome (VEBRAS) is an autosomal dominant condition associated with short stature, microcephaly, mild dysmorphic features, and learning disabilities. It was first described in 2018, and only 38 cases have been reported since then. All patients have mutation in the Glutamine-rich protein 1 (QRICH1) gene, yet clinical presentation has a broad spectrum and continues to expand. This report is of a mother and daughter pair with VEBRAS, associated with a new variant of the QRICH1 gene, NM_017730.3: c.337C>T; p.(Gln113*), and few previously undescribed phenotypic features.
CASE REPORT: We present 2 new cases, a mother and daughter, with novel heterozygous nonsense variant NM_017730.3: c.337C>T; p.(Gln113*). The daughter was referred to a geneticist at the age of 17 years because of seizures, dysmorphic features, and magnetic resonance imaging suggestive of leukodystrophy. In addition to already described clinical features, she had diffuse infantile hemangiomatosis and occipital balding. She was accompanied by her mother, who shared similar phenotypic features, raising suspicion for a similar genetic condition. Unlike the daughter, the mother never had any significant health problems or concerns and described herself as perfectly healthy. Genetic testing was performed in both individuals, and a novel pathogenic QRICH1 variant was discovered.
CONCLUSIONS: Considering the novelty of VEBRAS, every new clinical case contributes to the enlargement of the VEBRAS cohort, expanding the phenotypical and mutational spectrum, with potential improvement in the further care and observation of probands and their offspring. This report has highlighted the importance of clinical genetics in the identification of familial genetic disorders with complex phenotypes.
Keywords: Body Dysmorphic Disorders, cognitive dysfunction, genetic testing, Genome, Inheritance Patterns, Phenotype, QRICH1 Protein, Human
The first cases of intellectual disability combined with dysmorphic features and de novo heterozygous loss-of-function variants in the Glutamine-rich protein 1 (
The 17-year-old female patient was the first and only child of healthy non-consanguineous parents (Figure 1). Her mother gave no history of previous illnesses or substance misuse during pregnancy; however, she had a history of multiple miscarriages. The mother did not reported any history of preeclampsia, gestational diabetes, or other complications during pregnancy with the proband, who was born prematurely at gestational week 27 by caesarean section. Apgar scores were 2, 3, and 5 at minute 1, minute 5, and after resuscitation, respectively. Her birthweight was 1.139 kg, height 36 cm, and head circumference 25.5 cm. She developed early respiratory distress and was admitted to the Intensive Care Unit for mechanical lung ventilation. On day 14 after birth, hemangiomatosis appeared. She had proportionally short stature, multiple hemangiomas on the face, neck, and extremities, as well as a small tongue and narrow and high-arched palates. Her further motor and cognitive development were slightly delayed: she started crawling at the age of 6 months, at 12 months of age she was able to stand but only with support, and she started walking at 16 to 18 months of age, approximately. She had had mild right-sided paresis, suspectedly caused by perinatal hypoxic ischemic brain injury. At the age of 13 years, she was referred to a neurologist for the first time, with focal motor seizures in the hands, which progressed to bilateral tonic-clonic seizures. She was started on treatment with oxcarbazepine and levetiracetam; unfortunately, the initial doses were unknown (was currently on levetiracetam 1000 mg twice daily); however her electroencephalogram results worsened with time, showing epileptic encephalopathy and dysfunction with epileptiform elements. Magnetic resonance imaging (MRI) was performed, and she was referred to a geneticist at the age of 17 years to exclude inherited leucodystrophies.
On the first examination with the geneticist, her height was 155 cm, weight was 36 kg, and body mass index was 14.98 kg/m2. She had mild scoliosis, broad forehead, prominent long nose, hypertelorism, smooth philtrum, thin upper lip, hirsutism, and mild gaze deviation. Also, occipital balding was observed (Figure 2). On neurologic examination, she had mild spastic paresis in her right leg, with initial contractures in the Achilles tendon. She attended elementary school, but had difficulties with concentration and focusing on tasks. During examination, she avoided eye contact but was otherwise cheerful and communicative. Her mother reported no signs of aggressive behavior, although she noted that her daughter could appear easily irritated. She underwent repeated laser surgeries for her hemangiomatosis and did not have any signs of them felt.
The patient was a 49-year-old woman with no previous significant medical history other than multiple miscarriages. She was also the only child of healthy, unrelated parents and cannot recall any additional information about her birth. However, she remembered that her mother was short-statured, at 155 cm. Similar to her daughter in case 1, this patient had short stature, broad forehead, prominent nose, thin upper lip, and occipital balding (Figure 3). She could make eye contact during conversation; however, she was easily distracted and inconsistent answering questions. Considering her history of miscarriages, she had visited a gynecologist, but no objective reason for miscarriage was found, according to her.
All things considered, further genetic testing was recommended and offered to both mother and daughter. Also, MRI was performed in both patients, revealing periventricular, symmetric transverse relaxation time (T2) and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions in both hemispheres in the daughter (Figure 4). In the mother, the investigation did not reveal any specific brain matter lesions (Figure 5).
Considering the radiologic findings and clinical presentation, inherited leukodystrophy was suspected and a Blueprint Genetics Leukodystrophy and Leukoencephalopathy panel was performed; however, this analysis did not detect any known disease-causing mutations or novel variants that were considered deleterious. All things considered, we proceeded with whole exome sequencing, which identified a novel heterozygous variant in the QRICH1 gene, classified as pathogenic according to the American College of Medical Genetics 2015 criteria (the variant results in nonsense change and is predicted to undergo nonsense-mediated decay, and loss-of-function is a well-known disease mechanism for the QRICH1 gene [PVS1]; the variant is not present in gnomAD v2.1.1. or v3.1.1. [PM2]; the variant segregates with the phenotype in the family [PP1]). The variant was segregated in the mother using Sanger sequencing (Figure 6).
VEBRAS remains a rare entity with a large spectrum of pathogenic
Intellectual disability by itself may not be the reason to seek medical attention and perform additional investigations, as we can see in our patients. Unlike most of the previously reported cases, our patients were 17 and 49 years old at first evaluation with a geneticist, despite the premature birth and health problems during infancy in the patient in case 1. The summary of preceding cases shows that most were seen during the first decade of a patient’s life. Our case is similar to another case, which was also of maternal inheritance, and in our case, we can speculate about the mother’s cognitive impairment as a potential reason for lacking awareness of the child’s condition .
The first patients with described de novo variants in the
The overall function of the
The reported proband and her mother have some additional, previously undescribed features, including occipital balding, infantile hemangiomatosis, and probable impaired fecundity. Considering the novelty of
Another noteworthy aspect in this case was the gene panel of choice when we suspected an inherited disorder. As can be seen, initial presentation and radiologic features led us in the wrong direction, resulting in a diagnostic delay of at least a few months. It was not lifesaving or an essential amount of time in this case; nevertheless, any clinician should be watchful and avoid any postponements in diagnosis if possible. Today, genetic testing is becoming progressively available; however, it does not always give answers when it comes to rare disorders. Therefore, we suggest proceeding with whole exome sequencing prior to gene panel testing for unknown and potentially rare disorders with multiple organ system involvement.
This case highlights multiple diagnostic challenges of rare diseases with phenotypic variability. Considering the small number of previously described patients with a
FiguresFigure 1.. Family tree. A) The proband (case 1). B) The proband’s mother (case 2). E=nonsense variant NM_017730.3: c.337C>T; p.(Gln113*). Figure 2.. The proband (case 1). Note the prominent nose, hypertelorism, smooth philtrum, thin upper lip, small chin, and prominent occipital balding. Figure 3.. The proband’s mother (case 2). Note the prominent nose, smooth philtrum, thin upper lip, small chin, and initial occipital balding. Figure 4.. The proband’s magnetic resonance imaging showing periventricular symmetric transverse relaxation time (T2) and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions in both hemispheres. Figure 5.. Magnetic resonance imaging of the proband’s mother showing the absence of any specific brain matter lesions. Figure 6.. Sanger sequencing of NM_017730.3(QRICH1): c.337C>T; p.(Gln113*).
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