Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

Dingemans, Alexander J.M.; Truijen, Kim M G; Kim, Jung-Hyun; Alaçam, Zahide; Faivre, Laurence; Collins, Kathleen M.; Gerkes, Erica H.; Haelst, Mieke M. van; Laar, Ingrid M.B.H. van de; Lindstrom, Kristin; Nizon, Mathilde; Pauling, James; Heropolitańska-Pliszka, Edyta; Plomp, Astrid S.; Racine, Caroline A.; Sachdev, Rani; Sinnema, Margje; Skranes, Jon; Veenstra‐Knol, Hermine E.; Verberne, Eline A.; Silfhout, Anneke T. Vulto-van; Wilsterman, Marlon E F; Ahn, Eun-Young Erin; Vries, Bert B.A. de; Vissers, Lisenka E.L.M.

doi:10.1038/s41431-021-00960-4

Cited by 22 publications

(73 citation statements)

References 29 publications

(44 reference statements)

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“…Brain abnormalities and psychomotor development delay are described in most patients. Although there are no specific contraindications for regional anesthesia, general anesthesia is a method of choice in patients with limited cooperation and altered mental status [ 4 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…The signs include facial asymmetry, midface retraction, short philtrum, broad nasal bridge, or small mouth with a high-arched palate. Dental abnormalities are described in the literature [ 4 ]. Although airway management was not described in the literature, these factors should lead to an expectation of difficult airway management (DAM).…”

Section: Discussionmentioning

confidence: 99%

“…Musculoskeletal abnormalities are represented by hypotonia, short stature, skull abnormality, scoliosis or hemivertebrae, rib abnormalities or joint hypermobility, and contractures. Typical visceral malformations are urogenital abnormalities such as a horseshoe or unilateral kidney, cardiac abnormalities such as an atrial or ventricular septal defect, and gastrointestinal abnormalities [ 4 , 5 , 6 ]. The occurrence of these symptoms can lead to possible difficulties during perioperative management (IV line or arterial line cannulation and difficult airway management).…”

Section: Introductionmentioning

confidence: 99%

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Anesthesia of the Patient with Zhu-Tokita-Takenouchi-Kim (ZTTK) Syndrome: A Case Report

Hudec

Kosinová

2022

Children

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Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is an extremely rare multiorgan disorder, first described in 2015. Nowadays, about 50 patients with ZTTK syndrome have been reported, but there are no data about management during anesthesia. ZTTK syndrome patients can be indicated for surgery of musculoskeletal deformations and corrections of cardiovascular or urogenital malformations. This syndrome can be challenging for the anesthetic team based on the clinical manifestation of the syndrome. Because there are no recommendations for the management of these patients, anesthesiologists have to study typical symptoms, anatomy and possible expected changes in pathophysiology in perioperative period. One of the most dreaded anesthetic complications, the scenario “can not intubate, can not ventilate” could occur in these patients. The goal of this publication is to show options for anesthetic and perioperative management of this new rare syndrome with no published studies about management and approach in the perioperative period. The anesthetic team should choose the safest available approach. We present the first case report of anesthesia of a patient with ZTTK syndrome, a 7-year-old boy indicated for posterior neuromuscular scoliosis correction and fusion. This case describes the author’s experiences with anesthetic management and mentions possible early postoperative complications. Adequate understanding of this syndrome can reduce perioperative complications and improve patient outcomes after surgery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anesthesia of the Patient with Zhu-Tokita-Takenouchi-Kim (ZTTK) Syndrome: A Case Report

Hudec

Kosinová

2022

Children

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“…[6][7][8][9][10] The phenotypic spectrum of ZTTK syndrome has been highlighted in descriptions of .60 individuals. [2][3][4][5][11][12][13][14] The core neurologic phenotypes identified include moderate-to-severe intellectual disability, hypotonia, and epilepsy. Brain MR imaging, available for 41 published patients, typically demonstrate a range of nonspecific structural abnormalities.…”

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confidence: 99%

Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome

Halliday

Baynam

Ewans

et al. 2022

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia.MATERIALS AND METHODS: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities.RESULTS: Pathogenic variants in SON, causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria. CONCLUSIONS:The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.ABBREVIATIONS: PVNH ¼ periventricular nodular heterotopia; VUS ¼ variant of uncertain significance; WES ¼ whole-exome sequencing; WGS ¼ wholegenome sequencing; ZTTK syndrome ¼ Zhu-Tokita-Takenouchi-Kim syndrome U nderstanding of the distinctive phenotypic features of a rare syndromic disorder facilitates earlier diagnosis. This is particularly evident when genomic sequencing studies yield ambiguous findings, such as variants of uncertain significance (VUSs) in syndromic genes. 1 Moreover, characteristic phenotypic features, or "phenotypic handles," often guide focused investigations. Rare phenotypically heterogeneous disorders present a considerable challenge in this respect due to prior ascertainment biases and limited cohort sizes.Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM #617140) is a rare phenotypically heterogeneous disorder characterized by developmental delay and a wide array of congenital multisystem anomalies. Haploinsufficiency of SON, mediated by either truncating variants or whole-gene deletions, has been identified as the underlying cause of ZTTK syndrome. 2-5 SON encodes the RNA-binding protein SON and is constitutively expressed, though expression is enriched during early brain

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“…Identifying genotype-phenotype correlations in ultra-rare disease is often not possible. Dingemans et al report 52 people affected by ZTTK-syndrome (SON variants), describing phenotypic variability even among people with the same SON variant [3]. Even if precise genotype-phenotype correlations cannot be identified, describing the clinical spectrum of rare diseases is important.…”

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confidence: 99%

Good genotype-phenotype relationships in rare disease are hard to find

McNeill

2022

Eur J Hum Genet

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Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

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Cited by 22 publications

References 29 publications

Anesthesia of the Patient with Zhu-Tokita-Takenouchi-Kim (ZTTK) Syndrome: A Case Report

Anesthesia of the Patient with Zhu-Tokita-Takenouchi-Kim (ZTTK) Syndrome: A Case Report

Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome

Good genotype-phenotype relationships in rare disease are hard to find

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