123 e-Letters

  • Reponse

    To Angela E. Lin, medical geneticist, Mass General for Children (Massachusetts General Hospital. Thank you for your interest in our publication.
    We agree, as we mention as part of our conclusion, that surveillance regarding aorthopathy in JP-HHT is important. Danish patients with JP-HHT are systematically recommended cardiovascular assessment, including echocardiogram, in addition to HHT-and GI-surveillance.

  • Expanding the phenotype of SMAD4-HHT: Connective tissue abnormalities and severe cardiovascular disease

    We applaud the Danish registry's wonderful contribution to the field of SMAD4-HHT research. We would like to alert readers to our recent review of 19 individuals (one new) about the connective tissue features, and severe aortic and valvar disease (Gheewalla et al., 2022). In addition, we called attention to the opposing phenotypes of SMAD4-HHT and SMAD4-Myhre syndrome as a result of loss-of-function and gain-of-function pathogenic variants, respectively. The nearly simultaneous publication of our paper would have prevented inclusion in this current article.
    REFERENCE: Gheewalla, G. M., Luther, J., Das, S., Kreher, J. B., Scimone, E. R., Wong, A. W., Lindsay, M. E., & Lin, A. E. (2022). An additional patient with SMAD4-Juvenile Polyposis-Hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes. American journal of medical genetics. Part A, 10.1002/ajmg.a.62915. Advance online publication. https://doi.org/10.1002/ajmg.a.62915

  • Parental views of a Paediatric TP53 Surveillance Clinic

    Constitutional pathogenic variants in TP53 are associated with a significant paediatric tumour risk with up to 41% of affected people developing their first tumour by the age of 18 [1]. Recently published UK Clinical Genetics Group Guidelines recommend childhood surveillance for carriers of TP53 pathogenic variants including annual whole-body and brain MRI, 3-4 monthly abdominal ultrasound and review in a dedicated clinic [2]. Such surveillance has been ongoing at Great Ormond Street Hospital (GOSH) for over three years. Through seeking parental views, we demonstrated that the surveillance is generally acceptable for children and their families, with high levels of expressed satisfaction.

    It has long been recognised that hospital procedures may present a source of anxiety and psychological distress for children and their families [3]. Recent work by SIGNIFY reported in this journal has demonstrated that adult carriers of TP53 pathogenic variants generally experienced low levels of psychological morbidity around whole-body MRI and found it to be an acceptable intervention [4]. However, comparable data around children’s experiences did not exist. We were keen to understand more about children's and parents’ experience of this surveillance clinic, including any associated burden.

    24 families representing a total of 41 children under the care of the TP53 carrier clinic at GOSH were invited by telephone to take part in a semi-structured anonymous online sur...

    Show More
  • Letter to the Editor: “Biallelic variants in BRCA1 gene cause a recognizable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency”

    We appreciate the article by Chirita-Emandi at al (1).
    The authors showed the phenotype of nine patients with biallelic variants at BRCA1 gene associated with Fanconi anemia-like complementation group-S (MIM 617883). As it is a rare syndrome, the publication of articles describing the clinical characteristics and follow-up data are important to improve the knowledge and disseminate evidence-based information.
    In Chirita-Emandi’s article, one patient is first reported and eight are from previous studies. All patients had prenatal and postnatal growth failure, microcephaly, skin pigmentation lesions, facial dysmorphism and cancer family history. Eight presented mild developmental delay, and six had cancer. None presented bone marrow failure or immunodeficiency (1).
    In this letter, we would like to update the clinical case of one of these patients. In a previous article we reported a homozygous loss-of-function BRCA1 mutation in a 2.5-year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features (2). At 6 years-old, she evaluated with neurological symptoms and her skull tomography detected an expansive and infiltrative lesion in the encephalic trunk, compressing and displacing the IV ventricle and obliterating the prepontine cistern and the cerebellar angles. The lesion characteristics were suggestive of diffuse astrocytoma. Soon after a decompressive neurological surgery, this child died....

    Show More
  • Evidence for a mitochondrial disease phenotype due to APOO deletion.

    Evidence for a mitochondrial disease phenotype due to APOO deletion.
    Kumarie Latchman1*, Antoni Barrientos 2*

    1. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
    2. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
    *Corresponding authors

    The APOO (Apolipoprotein O) gene codes for MIC26, a subunit of the MICOS complex (mitochondrial contact site and cristae organizing system). APOO was recently reported as a novel mitochondrial disease locus upon identification of a loss-of-function missense variant, c. 350T>C , (p.I117T in MIC26 ) in a hemizygous male proband with mitochondrial myopathy, lactic acidosis, cognitive impairment, and autistic features. 1
    Here, we present a six-year-old African American male with a history of epilepsy, developmental delay, hypotonia, coordination and balance difficulties, cognitive impairment, autism disorder, and microcytic anemia. Birth history was unremarkable, and he walked at 24 months despite coordination and balance deficits. His vocabulary is less than ten words at six years old, and he does not recognize body parts, letters, or numbers. Laboratory findings include normal lactic acid, 1.8 (0.4-1.8 mmol/L), and creatine kinase 126 U/L (<160 U/L). Brain magnetic resonance image was unremarkable. Family history is positive for schizophrenia and intellectual disability in his mother and psychi...

    Show More
  • Barakat Syndrome
    Amin J Barakat

    Dear Editor,

    I read with interest the article by Muroya et al. [1].

    The authors mention that the inherited condition of hypoparathyroidism, sensorineural deafness and renal dysplasia has been recognized as a distinct clinical entity since the report by Bilous et al. in 1992. In fact, this syndrome was described for the first time in 1977 by Barakat et al. [2]. The syndrome with presumed autosomal rec...

    Show More
  • SDR9C7, KRT83, and increasing verisimilitude

    Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.

    We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.

    Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.

    With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consisten...

    Show More
  • Female carriers

    Fascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone

  • Response to 'Female carriers'

    Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies

  • KRT83 mutations are not associated with progressive symmetric erythrokeratoderma

    I recently came across this publication and was very surprised at some facts that seem inconsistent.
    Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
    First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
    In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
    To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...

    Show More