Two Novel HSD17B4 Heterozygous Mutations in Association With D-Bifunctional Protein Deficiency: A Case Report and Literature Review

Background: D-Bifunctional protein deficiency (D-BPD) is an autosomal recessive disorder caused by peroxisomal β-oxidation defects. According to the different activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units, D-bifunctional protein defects can be divided into four types. The typical symptoms include hypotonia and seizures. The gene that encodes D-BP was HSD17B4, which is located in chromosome 5q23.1.Case Presentation: We report the first case of D-BPD in a Chinese patient with neonatal onset. Cosmetic malformations, severe hypotonia and seizures are prominent. The blood bile acid profile showed increased taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid. Very-long-chain fatty acids (VLCFAs) revealed significant increases in hexacosanoic acid (C26:0), tetracosanoic acid/docosanoic acid (C24:0/C22:0), and hexacosanoic acid/docosanoic acid (C26:0/C22:0). Cranial MRI revealed bilateral hemispheric and callosal dysplasia, with schizencephaly in the right hemisphere. EEG showed loss of sleep–wake cycle and epileptiform discharge. Other examinations include abnormal brainstem auditory evoked potentials (BAEPs) and temporal pigmented spots on the optic disc in the right eye. After analysis by whole-exome sequencing, heterozygous c.972+1G>T in the paternal allele and c.727T>A (p.W243R) in the maternal allele were discovered. He was treated with respiratory support, formula nasogastric feeding, and antiepileptic therapy during hospitalization and died at home due to food refusal and respiratory failure at the age of 5 months.Conclusions: Whole-exome sequencing should be performed in time to confirm the diagnosis when the newborn presents hypotonia, seizures, and associated cosmetic malformations. There is still a lack of effective radical treatment. Supportive care is the main treatment, aiming at controlling symptoms of central nervous system like seizures and improving nutrition and growth. The disease has a poor outcome, and infants often die of respiratory failure within 2 years of age. In addition, heterozygous deletion variant c.972+1G>T and missense mutations c.727T>A (p.W243R) are newly discovered pathogenic variants that deserve further study.

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Peroxisomal D-bifunctional protein deficiency: Three adults diagnosed by whole-exome sequencing

Neurology ◽

10.1212/wnl.0000000000000219 ◽

2014 ◽

Vol 82 (11) ◽

pp. 963-968 ◽

Cited By ~ 39

Author(s):

M. A. Lines ◽

R. Jobling ◽

L. Brady ◽

C. R. Marshall ◽

S. W. Scherer ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Protein Deficiency ◽

Bifunctional Protein ◽

Whole Exome

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Slowly progressive d -bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.11.009 ◽

2017 ◽

Vol 372 ◽

pp. 6-10 ◽

Cited By ~ 4

Author(s):

Takashi Matsukawa ◽

Kagari Mano Koshi ◽

Jun Mitsui ◽

Taro Bannai ◽

Miho Kawabe ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Protein Deficiency ◽

Bifunctional Protein ◽

Whole Exome

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Fatal cardiomyopathy and hepatic dysfunction with acute onset due to mitochondrial trifunctional protein deficiency diagnosed by whole exome sequencing

Gineco eu ◽

10.18643/gieu.2015.8 ◽

2015 ◽

Vol 11 (1) ◽

pp. 8-11

Author(s):

Bratila E.

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hepatic Dysfunction ◽

Acute Onset ◽

Protein Deficiency ◽

Whole Exome ◽

Mitochondrial Trifunctional Protein ◽

Fatal Cardiomyopathy

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A Case of Mitochondrial Trifunctional Protein Deficiency with HADHB Variants Diagnosed Using Whole-Exome Sequencing

Annals of Child Neurology ◽

10.26815/acn.2021.00416 ◽

2021 ◽

Vol 29 (4) ◽

pp. 194-198

Author(s):

Chan Kim ◽

Dajeong Lee ◽

Jiwon Lee ◽

Sung Yoon Cho ◽

Jeehun Lee

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Protein Deficiency ◽

Whole Exome ◽

Mitochondrial Trifunctional Protein

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Identification of a Novel DICER1 Germline Mutation in Thyroid Follicular Adenoma Using Whole Exome Sequencing

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1819 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A891-A891

Author(s):

Chong Kun Cheon

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Germline Mutation ◽

Wilms Tumor ◽

Follicular Adenoma ◽

Cystic Nephroma ◽

Thyroid Lobe ◽

Whole Exome ◽

Exon 20 ◽

The Right

Abstract Backgrounds: DICER1 protein is a member of the ribonuclease III family of proteins that cleaves non-coding small RNA precursors to generate mature miRNAs, which in turn regulate gene expression post-transcriptionally. Thyroid abnormalities are frequently observed in DICER1 syndrome with multinodular goiter present in families in which a germline DICER1 mutation is segregating. Recently, we identified a germline DICER1 mutation in a family with multiple tumors using whole exome sequencing (WES). Methods and Materials: Following informed consent, WES of peripheral blood DNA was carried out on affected individual. Sanger sequencing was performed to confirm the DICER1 variant detected by WES and to assess her family for mutation in the same DICER1 exon (exon 20). Results: An 8 year-old girl presented with abdominal mass. Laparoscopic radical nephrectomy was done due to Wilms tumor. At age 12, palpable mass on the right thyroid lobe was found, and right hemithyroidectomy was performed. She was diagnosed with follicular adenoma, and she started to take levothyroxine. At age 13, palpable thyroid mass on the left thyroid lobe was identified, and total thyroidectomy was performed due to progressively enlarged remnant thyroid gland with multiple nodules. The pathological result was adenomatous goiter with a cystic change. During the evaluation, a 1.5cm follicular cyst in the left ovary, 0.7cm cystic lesion in the right middle lobe of the lung, and air-trappings in both lungs were observed. We performed WES which revealed a novel heterozygous missense mutation, c.3506C>G(p.S1169*) in exon 20 of the DICER1 gene. During the follow-up, she showed a severely enlarged right kidney with multiple septated cysts. Right total nephrectomy was done due to hemorrhage progression in cysts and biopsy revealed cystic nephroma. Continuous renal replacement therapy was applied after right nephrectomy, and maintenance hemodialysis was applied. Conclusions: We identified a novel DICER1 germline mutation in a family with thyroid follicular adenoma, Wilms tumor, and contralateral progressive cystic nephroma which is the first report in Korea.

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Partial gonadal dysgenesis associated with a pathogenic variant of PBX1 transcription factor

BMJ Case Reports ◽

10.1136/bcr-2018-227986 ◽

2019 ◽

Vol 12 (7) ◽

pp. e227986 ◽

Cited By ~ 1

Author(s):

Farnaaz Kia ◽

Kyriakie Sarafoglou ◽

Ashajyothi Mooganayakanakote Siddappa ◽

Kari D Roberts

Keyword(s):

Transcription Factor ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Situ Hybridisation ◽

Pathogenic Variant ◽

Cell Leukaemia ◽

Fluorescence In Situ Hybridisation ◽

Whole Exome ◽

Microscopic Evaluation ◽

The Right

A term neonate was admitted to the Neonatal Intensive Care Unit for respiratory distress, hypotonia and atypical genitalia. Significant findings included a small phallic structure, labial folds, no palpable gonads and two perineal openings. Pelvic ultrasound showed uterine didelphys and a gonad in the right inguinal canal. The right gonad was removed during diagnostic laparoscopy with microscopic evaluation showing infantile testicular tissue and fluorescence in-situ hybridisation showed only XY signal suggesting that the removed gonad was a male-developed testis. Infant was 46,XY, SRY probe positive. The parents chose a female sex assignment prior to gonadectomy. The infant had respiratory insufficiency and central hypotonia that persisted on discharge. Whole exome sequencing showed a heterozygous pathogenic variant of the PBX1 gene. This variant encodes the pre-B-cell leukaemia homeobox PBX transcription factor and has been associated with malformations and severe hypoplasia or aplasia of multiple organs including lungs and gonads. Whole exome sequencing was crucial in providing a unifying diagnosis for this patient.

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