• Users Online: 1010
  • Print this page
  • Email this page

 Table of Contents  
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 153-156

Case series: Three cases emphasizing importance of genetics in PICU

Department of Pediatrics, Army Hospital (Research and Referral), New Delhi, India

Date of Submission02-Nov-2020
Date of Decision04-Jan-2021
Date of Acceptance14-Jan-2021
Date of Web Publication21-May-2021

Correspondence Address:
Dr. Ashish Kumar Simalti
Army Hospital (Research and Referral), New Delhi - 110 010
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_174_20

Rights and Permissions

Individual genetic disorders are rare but cumulative prevalence of these disorders is high. Genetic diagnostic armamentarium has expanded with introduction of next generation sequencing techniques. A qualified geneticist can be of invaluable help in applying suitable genetic test and analyzing the results. We present 3 cases highlighting how involving qualified geneticist in daily round can help in detecting rare disorder even when clinical picture is not suggestive of a genetic disorder.

Keywords: Exome sequencing, genetic tests, geneticist, pediatric intensive care units

How to cite this article:
Dwivedi A, Simalti AK, Goswami JN, Kalra S, Negi V. Case series: Three cases emphasizing importance of genetics in PICU. J Pediatr Crit Care 2021;8:153-6

How to cite this URL:
Dwivedi A, Simalti AK, Goswami JN, Kalra S, Negi V. Case series: Three cases emphasizing importance of genetics in PICU. J Pediatr Crit Care [serial online] 2021 [cited 2023 Jun 2];8:153-6. Available from: http://www.jpcc.org.in/text.asp?2021/8/3/153/316592

  Introduction Top

Very often pediatric intensivists come across cases with unusual features which puzzle even the most experienced clinician. With rapid developments in the field of medical genetics, our ability to diagnose disorders with genetic basis has improved exponentially.[1] Genetic diagnostic armamentarium has expanded with introduction of next-generation sequencing techniques. For a general pediatrician or intensivist, sometimes it can be difficult to choose appropriate genetic test or interpret the results. A qualified geneticist can be of invaluable help in applying suitable genetic test and analyzing the results. We share our experience of how involving qualified geneticist in daily round can help in detecting rare disorder even when clinical picture is not suggestive of a genetic disorder.

  Case Reports Top

Case 1

Ten-month-old male infant, second born of nonconsanguineous parents, presented with recurrent generalized tonic-clonic seizures. There was no history of developmental delay, vision, or hearing impairment. There was no obvious dysmorphism. First episode of seizure was at 1 month of life. On evaluation, hypocalcemia was detected. Infant was managed with parenteral calcium followed by oral calcium and Vitamin D. He remained well on calcium supplements till 10 months of age when he had recurrence of seizures. Parents were very worried as his elder female sibling had expired at 10 months of life with a history of seizures. She had global developmental delay also, but further details were not available. On examination, index child was found to have age and gender appropriate height, weight, and head circumference. Investigations revealed hypocalcemia again. On further evaluation, he was found to have low parathormone levels, low magnesium, and high phosphate [Table 1]. Child was managed with calcium, Vitamin D, and magnesium supplements.
Table 1: Summary of relevant investigations in Case 1

Click here to view

In view of two siblings affected, the possibility of underlying genetic cause was suggested by geneticist. Clinical exome sequencing was ordered which revealed pathogenic variation in the TRPM6 gene [Table 2]. Exome sequencing revealed two heterozygous nonsense variants in compound heterozygous state in TRPM6 (NM_017662.4) gene (c.2634C>A; p. Tyr878Ter (exon 20) and c.5827C>T; p. Gln1943Ter (exon 37). Parents are asymptomatic carriers. Based on the clinical features, laboratory investigations, and molecular testing, Child was diagnosed to have Familial hypomagnesemia with secondary hypocalcemia (TRPM 6 related). It is an autosomal recessive condition characterized by very low serum magnesium.[2] Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency (Magnesium is required for the production and release of parathyroid hormone). Shortages of magnesium and calcium can cause neurological problems that begin in infancy, including painful muscle spasms (tetany) and seizures.[3] If left untreated, hypomagnesemia with secondary hypocalcemia can lead to failure to thrive, developmental delay, and may even lead to cardiac failure. Treatment involves lifelong magnesium supplements. Final diagnosis was familial hypomagnesemia with secondary hypocalcemia (TRPM6 related)
Table 2: Result of exome sequencing case 1

Click here to view

Case 2

Two-month-old baby, firstborn of nonconsanguineous parents, presented to a peripheral health care setup with bronchiolitis-like picture. The baby was identified to have tachycardia with heart rate of 240 beats per minute and on electrocardiogram (ECG) supraventricular tachycardia was seen which was reverted to sinus rhythm after two incremental aliquots of rapid flush adenosine. Laboratory investigations showed a normal basic metabolic panel with normal renal function tests, except for the elevated potassium levels between 6 and 6.8 mEq/L. ECG was unremarkable for signs of hyperkalemia such as peaked T-waves. Echocardiography revealed a structurally normal heart with good biventricular function. However, chest X-ray showed diffuse nonhomogenous opacities suggestive of bronchiolitis and a large homogenous opacity silhouetting the left cardiac border with a linear translucency surrounding it. Tumor lysis syndrome was initially suspected to be the cause of hyperkalemia but contrast-enhanced computed tomography of the chest revealed that anterior medicinal mass was an unusually large, hypertrophied thymus gland and not a malignant mass. During the pediatric intensive care unit (PICU) stay, the baby remained asymptomatic but continued to have hyperkalemia. The baby was worked up for plasma renin activity and aldosterone levels for possibility of pseudohypoaldosteronism. However, all reports were within normal limits including 17 hydroxy progesterone levels. There were no dysmorphic features or abnormal genitalia suggestive of any obvious syndrome. Common causes of pseudohyperkalemia (cell lysis, extreme leukocytosis or thrombocythemia, or the use of ethylenediaminetetraacetic acid anticoagulant) were ruled out.

Clinical exome sequencing was done to hunt for the cause of hyperkalemia. It revealed pathogenic heterozygous variation (c.592G>T, p. Gly198Trp) in the abcb6 gene [Table 3] which is associated with Autosomal dominant familial pseudohyperkalemia Type 2. This is a benign disorder associated with temperature-dependent anomaly in red cell membrane permeability to potassium that leads to high in vitro potassium levels in samples stored <37°C.[4],[5] The diagnosis was confirmed by doing parallel laboratory assessment of serum potassium levels incubated at 37°C and 4°C which revealed normal potassium levels at 37°C (4.8 mEq/L) and hyperkalemia at 4°C (6.0 mEq/L). Maternal sample did not reveal abnormality, while father was not available for testing. Final diagnosis was Autosomal dominant familial pseudohyperkalemia Type 2.
Table 3: Result of exome sequencing case 2

Click here to view

Case 3

Four-month-old female infant, firstborn of nonconsanguineous parents, was brought with complaints of not responding to mother and drowsiness for past 2 days. On examination, the baby was found to be comatose, no vocalization and withdrawal on painful stimuli. On taking detailed history, it was found that the baby had similar episode of altered sensorium at 1 month of age when she was admitted at another hospital for about 1 month and the child was discharged against medical advice in comatose condition. According to mother baby had improved over the next 2 months at home but deteriorated again for the past 2 days. She was intubated in view of poor sensorium. In view of the episodic nature of illness, inborn error of metabolism was considered and baby was kept nil per mouth and maintained with intravenous fluid. However, IEM workup including blood gases, ammonia, tandem mass spectrometry , and gas chromatographymass spectrometry were normal and she was restarted on nasogastric feeds. During the 1st week of PICU stay, the central line was changed thrice in a week because of thrombosis, and ultrasound Doppler also confirmed the presence of thrombus at sites of central venous cannulation. Paradoxically, her prothrombin time was deranged with the international normalized ratio being in range of 5–6 every time. Clinically, there was no evidence of coagulopathy. MRI was done which revealed gross hydrocephalus with marked thinning of brain parenchyma and sequelae of intraventricular and subarachnoid hemorrhage. In view of this VP, shunt was also done. However, her condition continued to deteriorate and she never regained consciousness. She continued to worsen and succumbed to illness 19 days after admission.

Exome sequencing identified homozygous missense variation (c.904GG>A, p.Asp302Asn) in F7 gene [Table 4]. This is a known pathogenic variation. Factor VII deficiency is characterized by bleeding diathesis, intracranial hemorrhage, etc., Thrombus formation is also known in factor VII deficiency due to unidentified reasons.[6],[7] Final diagnosis was Factor VII deficiency.
Table 4: Result of exome sequencing case 3

Click here to view

  Discussion Top

Rare genetic disorders may not be very obvious on admission and only with a high index of suspicion, it can be unmasked.[8] Suspicion may arise in the presence of unusual features, or unusual response to treatment. Uncertainty about diagnosis and often prognosis contributes to the difficulty of planning optimal care. Role of genomic sequencing in pediatric critical care units is expanding to diagnose nonspecific, genetically heterogenous conditions for which rapid diagnosis impacts clinical decision-making process and/or treatment in the intensive care unit.[9] Achieving a rapid molecular diagnosis in critically ill children with a rare genetic disease may improve the basis for such plans including institution of specific treatment or withdrawal/avoidance of ineffective treatment. Definite molecular diagnosis enables accurate genetic counseling and ends the diagnostic odyssey.[10]

In our first case, molecular diagnosis of familial hypomagnesemia with secondary hypocalcemia helped indefinite management in the form of magnesium supplements and obviated the need for high doses of calcium supplementation which may be associated with nephrocalcinosis in long term.

Diagnosis of familial pseudohyperkalemia (benign asymptomatic condition) in second case, relieved the anxiety of treating pediatricians and parents. Knowing the exact nature of disorder by genomic sequencing prevented further investigations, monitoring, and unwarranted treatment.

Definite diagnosis of factor VII deficiency in the third case helped inaccurate genetic counseling and option of prenatal diagnosis could be provided for the next pregnancy as the disorder is usually severe in nature.

Usual turnaround time for exome sequencing is around 4 weeks, however, in patients with strong suspicion of underlying genetic disorder, rapid exome sequencing can be performed with reporting time of 10 days. Definitive molecular diagnosis helps in prognostication, management, and accurate genetic counseling. In a short span of 5 months, with the availability of clinical geneticist in daily PICU rounds, we diagnosed few rare conditions. Underlying genetic etiology was unveiled by genomic sequencing in all these cases. Appropriate choice of genetic test was suggested by geneticist which was based on the provisional diagnosis. These cases highlight the importance of definite diagnosis in this molecular era. It also emphasizes the role of trained geneticist in deep phenotyping and choosing the appropriate genetic tests from genetic diagnostic armamentarium.

Individual genetic disorders are rare but cumulative prevalence of these disorders is high. Genetic disorders should be suspected in the presence of unusual phenotype, inadequate response to standard treatment, and in the presence of positive family history. Involvement of clinical geneticist and rapid availability of genetic testing improves overall outcome in pediatric critical care units.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Hill M, Hammond J, Lewis C, Mellis R, Clement E, Chitty LS. Delivering genome sequencing for rapid genetic diagnosis in critically ill children: Parent and professional views, experiences and challenges. Eur J Hum Genet 2020;28:1529-40.  Back to cited text no. 1
Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2002;31:171-4.  Back to cited text no. 2
Pronicka E, Gruszczyńska B. Familial hypomagnesaemia with secondary hypocalcaemia — autosomal or X-linked inheritance? J Inherit Metab Dis 1991;14:397-9.  Back to cited text no. 3
Sugimoto T, Kume S, Osawa N, Nakazawa J, Koya D, Kashiwagi A. Familial pseudohyperkalemia: A rare cause of hyperkalemia. Intern Med 2005;44:875-8.  Back to cited text no. 4
Andolfo I, Russo R, Manna F, De Rosa G, Gambale A, Zouwail S, et al. Functional characterization of novel ABCB6 mutations and their clinical implications in familial pseudohyperkalemia. Haematologica 2016;101:909-17.  Back to cited text no. 5
Ramdass SK, Loh KP, Howard LM. Thrombosis in a bleeding disorder: Case of thromboembolism in factor VII deficiency. Clin Case Rep 2017;5:277-9.  Back to cited text no. 6
Mariani G, Bernardi F. Factor VII deficiency. Semin Thromb Hemost 2009;35:400-6.  Back to cited text no. 7
Carey AS, Chung WK. Genomic sequencing for infants and children in intensive care units. Curr Pediatr Rep 2019;7:78-82.  Back to cited text no. 8
Borghesi A, Mencarelli MA, Memo L, Ferrero GB, Bartuli A, Genuardi M, et al. Intersociety policy statement on the use of whole-exome sequencing in the critically ill newborn infant. Ital J Pediatr 2017;43:100.  Back to cited text no. 9
Ayres S, Gallacher L, Stark Z, Brett GR. Genetic counseling in pediatric acute care: Reflections on ultra-rapid genomic diagnoses in neonates. J Genet Couns 2019;28:273-82.  Back to cited text no. 10


  [Table 1], [Table 2], [Table 3], [Table 4]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Case Reports
Article Tables

 Article Access Statistics
    PDF Downloaded69    
    Comments [Add]    

Recommend this journal