Monogenic Diabetes is relatively rare, representing only 1-2&#x25; of total diabetes cases; nevertheless, it is often misdiagnosed primarily as type 1 diabetes, leading to unnecessary insulin therapy and delayed recognition of affected family members. In the present article, we describe a case of a young, male patient who presented with hyperglycemia in the absence of ketosis and following genetic testing; he proved to harbor the loss-of-function p.Arg1353His (c.4058G&#x3e;A) mutation in the ABCC8 gene, inherited from his mother. This mutation has been previously described in patients with Congenital Hyperinsulinism. Furthermore, different mutations in the ABCC8 gene have been linked with MODY 12, type 2, and gestational diabetes; however, to the best of our knowledge, this is the first report that associates this specific mutation with diabetes phenotype. ABCC8-related diabetes is characterized by remarkable heterogeneity in terms of clinical presentation and therapeutic approach. Early diagnosis and individualized treatment are essential to achieving metabolic targets and avoiding long-term diabetes complications.

Theocharis Koufakis

Amalia Sertedaki

Elizabeth-Barbara Tatsi

Christina-Maria Trakatelli

Spyridon N. Karras

Eleni Manthou

Christina Kanaka-Gantenbein

Kalliopi Kotsa

First Report of Diabetes Phenotype due to a Loss-of-Function ABCC8 Mutation Previously Known to Cause Congenital Hyperinsulinism

The NAA10-related syndrome is a rare X-linked neurodevelopmental condition that was first described in 2011. The disorder is caused by pathogenic variants in the NAA10 gene located on chromosome X at position Xq28. Clinical features typically include severe psychomotor developmental delay, cardiac disease, dysmorphic features, postnatal growth failure, and hypotonia, although there is significant variability in the severity of the phenotype among affected individuals. We describe a 5-year-old female with the syndrome; massively parallel exome sequencing and analysis revealed the c.247C&#x3e;T (p.Arg83Cys) pathogenic variant that has been previously reported in ten affected individuals. Ocular manifestations of the NAA10-related syndrome are not uncommon, although they have not been well characterized in literature reports. From a systematic review of previously published cases to date, ocular abnormalities are present in more than half of patients with the syndrome. Common ocular findings reported include astigmatism, hyperopia, cortical vision impairment, microphthalmia/anophthalmia, and hypertelorism. Our patient presented with growth restriction, dysmorphic features, and hypotonia. Ocular manifestations identified in this child include downslanting palpebral fissures, myopic astigmatism, nystagmus, and exotropia. We speculate that the type and severity of ocular defects present in individuals with the NAA10-related syndrome are dependent on the specific NAA10 pathogenic variant involved.

Angela S. Gupta

Hind Al Saif

Jennifer M. Lent

Natario L. Couser

Ocular Manifestations of the NAA10-Related Syndrome

The anomalies of X chromosome are classified as numerical or structural. Concomitant structural anomalies in this chromosome that associate partial loss of its long arm with duplications in its short arm are uncommon. Only a few cases have been published and in most of them the reported patients present ovarian dysfunction, tall stature, and overdosage of the SHOX gene with locus Xp22.33. Considering these reports, we evaluated the case of a woman with a deletion in the long arm of the X chromosome, premature ovarian failure, tall stature, and multiple arterial vascular disease. With the aim to find a relationship between karyotype and phenotype, we explored associated anomalies in Xp and certified the overdosage of the SHOX gene in this case by MLPA. Also, taking into account the fact that the gene locus of the angiotensin-converting enzyme type 2 (ACE2) is located in Xp, our goal was to investigate the influence of this gene in the development of cardiovascular disease. The detection of the gene product of ACE2 by ELISA was undetectable. We have proposed that cytogenetic anomalies in X chromosome could contribute to decrease this protein synthesis in this gender.

J. M. Ramirez

F. A. Rodr&#xed;guez

M. I. Echeverr&#xed;a

A. L. Vargas

A. E. Calder&#xf3;n

R. M. Miatello

N. F. Renna

SHOX Duplication and Tall Stature in a Patient with Xq Deletion and Vascular Disease

Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to GLI3 gene mutations classically characterized by the presence of a hypothalamic hamartoma and polydactyly. Additional diagnostic criteria include bifid epiglottis, imperforate anus, small nails, hypopituitarism, growth hormone deficiency, and genital hypoplasia. It is typically diagnosed in infancy and early childhood, presenting with seizures and/or precocious puberty due to the hypothalamic hamartoma, and with limb anomalies due to central polydactyly. Our patient had presented with polysyndactyly at birth. However, as this is not uncommon in infants and is usually as part of the sporadic, isolated form of polydactyly, no further work up was done. He then presented at age 16 years with a headache and subjective visual changes, with brain imaging revealing a hypothalamic hamartoma. He did not have a history of seizures or central precocious puberty. Genotyping revealed a pathogenic variant affecting the GLI3 gene. We encourage all clinicians to consider PHS or an associated syndrome with a clinical finding of polydactyly. Further, as the natural history continues to reveal itself, this patient&#x2019;s presentation provides important new data to the broad phenotypic spectrum of PHS.

Aria Mahtabfar

Niall Buckley

Susan Murphy

Shabbar Danish

Ian Marshall

Pallister-Hall Syndrome Presenting in Adolescence

We report a heterozygous, 2,009 base pairs (bps) genomic DNA deletion within the SERPING1 gene that has not previously been reported in a case of type I hereditary angioedema (HAE). The patient is a 28-year-old Han Chinese female living in Hong Kong who has suffered from recurrent angioedema since adolescence, with increasing attack frequency as she entered adulthood; in the past, episodes occurred annually, but now occur every two to three months. The affected areas are not itchy and include common sites such as the left and right forearms, but without throat involvement. The patient also experiences epigastric pain. The patient&#x2019;s mother suffers from similar symptoms. A mutation in the serine protease inhibitor, clade G, member 1 (SERPING1) gene is associated with HAE. Patients with HAE type I commonly carry either a small deletion within SERPING1 or a truncated transcript. We performed a multiplex ligation-dependent probe amplification (MLPA) assay on our indexed patient. Our result suggests a 2,009 bps deletion spanning across exons 5 and 6 within SERPING1. Although earlier literature has described other large DNA deletions encasing exons 5 and 6 in SERPING1, these DNA rearrangements were larger in size between 4 and 6 kbps, and the breakpoint locations were generally not determined due to technical constraints (Pappalardo et al., 2000; Duponchel et al., 2001; Roche et al., 2005; Loules et al., 2018; and G&#xf6;&#x3b2;wein et al., 2008). Our report describes mapping of this 2,009 bps in SERPING1. Using a combination of molecular techniques, we were able to confirm and locate this large heterozygous genomic DNA deletion that includes both exons 5 and 6 of SERPING1.

Wai-Yu Wong

Helen Wong

Elaine Au

Eric Chan

Identification and Mapping of a 2,009-bp DNA Deletion in SERPING1 of a Hereditary Angioedema Patient

Werner&#x2019;s syndrome (WS) is an autosomal recessive genetic disease, which is mainly characterized by scleroderma-like skin changes, juvenile cataracts, short stature, and signs of premature aging. We report a case of a 48-year-old male patient, who presents with cardinal signs of WS including high-pitched voice, sclerotic skin lesions mainly on feet, premature greying of scalp hair, bilateral cataracts, and &#x201c;bird-like&#x201d; facial appearance. In addition, the patient presents other clinical characteristics observed in patients with WS such as short stature, type 2 diabetes mellitus, hypogonadism, parental consanguinity, and a history of a sibling with similar clinical characteristics. WRN gene sequencing identified the homozygous pathogenic variant NM&#x5f;00553.4: c.2581C&#x3e;T (NP&#x5f;000544.2: pGln861Ter). This is the first case of WS reported in the Colombian population. We report this case to avoid misdiagnosis of this infrequent condition and allow timely identification of potential complications associated with premature aging, especially malignancies, cardiovascular and metabolic diseases.

A. Rinc&#xf3;n

L. Mora

F. Suarez-Obando

J. A. Rojas

Werner&#x2019;s Syndrome: Understanding the Phenotype of Premature Aging&#x2014;First Case Described in Colombia

8q22.2q22.3 microdeletion syndrome has been described in only seven patients. We present a new case from Colombia. The characteristics of this condition are developmental delay, microcephaly, seizures, and typical facial dysmorphism. We discuss the clinical phenotype of the patient presenting relevant findings like hearing loss and severe epilepsy and the possible relations between the phenotype and the genes involved in the microdeletion. We describe a female with developmental delay, microcephaly, epilepsy, severe short stature, impaired speech, facial dysmorphism, and congenital deafness. A minimal/maximal deletion of 5.238 Mb and 5.374Mb, respectively, at 8q22.2q22.3 was diagnosed using a genome-wide array. The clinical phenotype is similar to the others seven patients previously reported; however, the severity of epilepsy and the concomitant hearing loss is remarkable, characteristics previously observed independently in only two patients. The KCNS2 gene is located in the deleted regions (8q22.2). Therefore it is a possible candidate for explaining the complex neurologic phenotype.

Alejandra Rincon

Paola Paez-Rojas

Fernando Su&#xe1;rez-Obando

8q22.2q22.3 Microdeletion Syndrome Associated with Hearing Loss and Intractable Epilepsy

A 62-year-old female had suffered from recurrent syncopal episodes triggered by physical and emotional stress since childhood. She had no family history of sudden death. An intensive examination could not detect any structural disease, and exercise stress testing provoked polymorphic ventricular ectopy followed by polymorphic ventricular tachycardia accompanied with syncope leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). A genetic analysis with a next generation sequencer identified a homozygous W361X mutation in the CASQ2 gene. Careful history taking disclosed that her parents had a consanguineous marriage. Here we present a Japanese patient with a recessive form of CPVT.

Taishi Fujisawa

Yoshiyasu Aizawa

Yoshinori Katsumata

Akihiro Udo

Shogo Ito

Kazumasa Hatakeyama

Makoto Hirose

Hiroshi Miyama

Kazuaki Nakajima

Takahiko Nishiyama

Takehiro Kimura

Masamitsu Nitta

Kazuo Misumi

Seiji Takatsuki

Kenjiro Kosaki

Keiichi Fukuda

A Homozygous CASQ2 Mutation in a Japanese Patient with Catecholaminergic Polymorphic Ventricular Tachycardia

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Case Reports in Genetics publishes case reports and case series focusing on diseases caused by hereditary predisposition or genetic variation in individuals and families.

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Case Reports in Genetics - Table of contents 2019

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Case Reports in Genetics publishes case reports and case series focusing on diseases caused by hereditary predisposition or genetic variation in individuals and families.

Case Reports in Genetics