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\begin{document}

\title{MEN-2A in a pregnant female during the COVID pandemic: A double whammy?}



\author[1]{Aarti Chitkara}%
\author[1]{Anubhuti Rana}%
\author[1]{Setu Gupta}%
\author[1]{Vidushi Kulshrestha}%
\author[1]{ArunRaj  Thankarajan}%
\author[2]{Vatsla Dadhwal}%
\affil[1]{All India Institute of Medical Sciences}%
\affil[2]{All India Institute of Medical Sciences, New Delhi, India.}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\textbf{INTRODUCTION}

Multiple Endocrine Neoplasia (MEN) 2A is an autosomal dominant syndrome
characterized by medullary thyroid carcinoma (MTC), pheochromocytoma
(PCC) and parathyroid tumors.{[}1-4{]} Caused by germ-line mutation in
the RET proto-oncogene located on chromosome 10, MEN-2A is a subtype of
the MEN-2 syndrome and is the more commonly encountered clinical variant
(accounting for 75\% cases) as opposed to MEN-2B.{[}5,6{]} Almost 90\%
afflicted individuals manifest with MTC while PCC and parathyroid tumors
are noted in upto 40-50\% and 20-30\% cases respectively. As the disease
may present with polyglandular involvement, screening of other endocrine
organs is imperative once any single organ involvement is detected.
Current literature on diagnosis and management of MEN-2A syndrome in
pregnancy is scant and largely comprises case series or case reports.
Most patients were incidentally detected to have hypertension during
routine antenatal screening and found to have an underlying
pheochromocytoma. The limitations imposed by pregnancy both in terms of
restricted imaging options due to radiation exposure to the fetus and
restricted period of surgical intervention in the second trimester makes
the management of this situation challenging in most cases. We share our
experience of a young woman with MEN 2A syndrome who became pregnant
immediately post adrenalectomy for pheochromocytoma and had to undergo
surgery for medullary thyroid carcinoma in second trimester during a
nationwide lockdown due to the ongoing COVID pandemic. The case
highlights the various challenges we faced in patient management,
surgical intervention, post-operative care and follow up amidst travel
restrictions during the lockdown along with how these challenges were
overcome through multidisciplinary teamwork, teleconsultation services
and shared decision making with the patient which led us to a successful
outcome in a difficult clinical scenario, in such challenging times.

\textbf{METHODS AND RESULTS}

Our patient was a 20-year-old lady who had initially presented to the
medicine outpatient services at an outside hospital in September 2019
for recurrent episodes of palpitations, headaches and abdominal pain. On
imaging she had been detected to have bilateral adrenal masses. Due to
the high prevalence of tubercular adrenalitis in India, she had been
given a trial of empirical anti-tubercular therapy, which had been
unsuccessful and she was subsequently referred to the Medicine
department of our institute for further evaluation. Review of her
clinical history and imaging led us to suspect the possibility of a
pheochromocytoma which was confirmed by the elevated catecholamine
levels noted in her urine along radiological evidence with 68Ga-DOTANOC
PET/CT
{[}68Ga-Labeled(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraaceticacid)-1-NaI3-octreotide-
positron emission tomography/computed tomography{]} which were
consistent with bilateral pheochromocytoma (Table S1 and Figure 1, S2).

Considering the occurrence of bilateral pheochromocytoma at a young age
(seen in only 10\% cases), the possibility of MEN syndrome was kept, and
further evaluation was performed. Ultrasound (USG) neck revealed
bilateral thyroid nodules and parathyroid adenoma. Fine needle
aspiration cytology (FNAC) of the thyroid nodules revealed MTC thus
completing the classical triad of MEN 2A syndrome. In light of these
findings, the patient's family history was reviewed but was
noncontributory.

Our patient was a 20-year-old lady who had initially presented to the
medicine outpatient services at an outside hospital in September 2019
for recurrent episodes of palpitations, headaches and abdominal pain. On
imaging she had been detected to have bilateral adrenal masses. Due to
the high prevalence of tubercular adrenalitis in India, she had been
given a trial of empirical anti-tubercular therapy, which had been
unsuccessful and she was subsequently referred to the Medicine
department of our institute for further evaluation. Review of her
clinical history and imaging led us to suspect the possibility of a
pheochromocytoma which was confirmed by the elevated catecholamine
levels noted in her urine along radiological evidence with 68Ga-DOTANOC
PET/CT
{[}68Ga-Labeled(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraaceticacid)-1-NaI3-octreotide-
positron emission tomography/computed tomography{]} which were
consistent with bilateral pheochromocytoma (Table 1 and Figure 1-2).

Considering the occurrence of bilateral pheochromocytoma at a young age
(seen in only 10\% cases), the possibility of MEN syndrome was kept, and
further evaluation was performed. Ultrasound (USG) neck revealed
bilateral thyroid nodules and parathyroid adenoma. Fine needle
aspiration cytology (FNAC) of the thyroid nodules revealed MTC thus
completing the classical triad of MEN 2A syndrome. In light of these
findings, the patient's family history was reviewed but was non
contributory.

The patient was reviewed by the surgery and endocrinology services at
our centre and was planned for bilateral adrenalectomy followed by total
thyroidectomy for definitive management of her condition in two
sittings. The patient underwent a laparoscopic transperitoneal
adrenalectomy with a plan to perform a thyroidectomy for MTC in the next
sitting. Histopathological examination of the adrenal glands confirmed
the diagnosis of pheochromocytoma. However, India entered a nationwide
lockdown from 24\textsuperscript{th} March 2020 in view of the COVID-19
pandemic and massive reorganization occurred in the government
healthcare system. Outpatient services were restricted and largely
replaced by teleconsultation services were offered to outpatients. All
elective surgeries were deferred and only emergency procedures were
being performed with a large number of physicians being diverted to
centres dedicated to the management of the burgeoning load of patients
afflicted with COVID-19 pneumonia.{[}7{]} Considering the exceptional
situation at hand the patient was discharged and asked to follow up
through teleconsultation for her second surgery. She was kept on
glucocorticoids (Tablet Prednisolone 5 mg once a day) and
mineralocorticoids (Tablet Fludrocortisone 100 mcg once a day). However,
she conceived in her subsequent menstrual cycle in April 2020. This
posed a unique challenge of delivering appropriate antenatal care and
following up with the patient closely to optimize her for surgery, which
was now deferred to the second trimester of her pregnancy. These
services were provided by a multidisciplinary team comprising her
treating obstetricians, endocrinologists and surgeons. Her first
trimester was uneventful and she successfully underwent a near total
thyroidectomy with level IV lymph node dissection and right inferior
parathyroid adenectomy in October 2020 at 24 weeks period of gestation
(POG). The histopathology revealed bilateral medullary thyroid carcinoma
each measuring 0.5 x 0.5 x 0.3 cm with lympho-vascular invasion and no
lymph node involvement along with right parathyroid adenoma (1 x 0.5 x
0.5 cm). Post-operative period was uneventful and she was discharged on
thyroid replacement therapy (Tab Thyroxine sodium 75 mcg/day).
Coincidentally there was a gradual downregulation of travel restrictions
at this time which made it easier for the patient to access healthcare
services provided at our centre. Unfortunately, in the postoperative
period she developed a mild COVID-19 infection at 27 weeks and was
admitted at our COVID facility, where close maternal and fetal
surveillance was done by a dedicated obstetric team. Her recovery was
uneventful and she continued to follow up with the treating team post
COVID through teleconsultation. She sought confinement at 36 weeks of
gestation with pre-eclampsia without severe features, intrahepatic
cholestasis of pregnancy (ICP) and late onset fetal growth restriction
and a decision was taken to terminate her pregnancy by cesarean section
at 37 weeks of gestation due to fetal bradycardia. She delivered a
healthy female child weighing 2380 grams ( appropriate for gestational
age) with an APGAR score of 9, 9. She received an intravenous stress
dose of hydrocortisone during peripartum period.

\textbf{OUTCOME AND FOLLOW-UP}

Both mother and baby were discharged in healthy condition and the
patient has undergone genetic testing, the results of which are awaited.

\textbf{COMMENTS}

MEN 2 is an autosomal dominant disorder with an estimated prevalence of
2.5 per 100,000.{[}8{]} Activating germline mutations of the RET
proto-oncogene are present in 98\% of the families of MEN-2 patients.
There is a strong genotype- phenotype correlation between a specific RET
mutation and its clinical course, with some genotypes being associated
with aggressive disease. The overall rarity of this syndrome along with
scant literature available on its management in pregnancy posed
significant challenges for the treating team. This was further
compounded by the COVID-19 pandemic and diversion of healthcare
resources for managing those afflicted which made it very difficult to
provide individualized care, which is mandated in such cases. To the
best of our knowledge, ours is the first case of pregnancy in a patient
with MEN-2A syndrome to be successfully managed and reported.

The primary step is management of pheochromocytoma, which, if left
untreated, may have devastating consequences and is associated with high
maternal and fetal morbidity and mortality. As it presents with
hypertension, it is often misdiagnosed as pre-eclampsia in the earlier
stages of pregnancy{[}9{]} Most cases of MEN 2A in pregnancy reported
till date presented with PCC crisis mandating the need to undergo
adrenalectomy. Our patient was fortunately diagnosed prior to conception
and underwent adrenalectomy prior to an unplanned conception. These
patients need glucocorticoid and mineralocorticoid replacement therapy
as received by our patient postoperatively.

MTC is the next challenge to tackle owing to the aggressive and
malignant nature of the disease. The impact of newly diagnosed MTC in
pregnancy is unknown and no major guidelines are available to guide
management of the same in pregnancy.{[}10{]} Our patient conceived
spontaneously while awaiting surgery for MTC, which forced us to delay
our surgical intervention till the second trimester. During this time,
we followed up out patient with serial serum calcitonin levels which is
generally used in postoperative follow up as recommended by ATA.{[}11{]}
However, it is important to highlight that a rise in calcitonin or even
its doubling time must be interpreted with caution in pregnant females
due to physiological increase in calcitonin during pregnancy.{[}12{]}
Delays in management of MTC are known to be associated with poorer
outcomes. This, along with the difficulty in monitoring pre-operatively
with serum calcitonin values, led us to pursue the surgery in the second
trimester.{[}10{]} Planning an elective surgery during the ongoing
pandemic where the entire healthcare infrastructure was restructured for
COVID management posed several logistic issues which were dealt with
successfully by the treating team and administration services of our
centre.

\emph{Tewari et al} (2001) described a case report of a 22-year-old
primigravida who was diagnosed with MEN 2A in her first trimester and
underwent adrenalectomy followed by thyroidectomy during her second
trimester and had successful maternal and fetal outcome at
term.{[}13{]}\emph{Sarathi et al} in 2011 described a 21-year-old
primigravida presenting with PCC crisis at 12 week's gestation and was
diagnosed with MEN 2A and RET mutation (C634W).{[}14{]} She successfully
underwent bilateral adrenalectomy followed by thyroidectomy during her
second trimester with calcitonin levels 713 pg/ml preoperatively and
32.6 pg/ml postoperatively. A larger case series of ten patients with
pheochromocytoma in pregnancy was described by \emph{Donatini et al} in
2018, out of which three patients had MEN 2A. Two of them had undergone
thyroidectomy for MTC prior to pregnancy and one patient had PCC crisis
at 27 weeks POG, for which she underwent unilateral adrenalectomy along
with total thyroidectomy and central neck dissection at 28 week's
gestation. Her Ctn levels before and after surgery were 311 pg/ml and
95.7 pg/ml respectively.{[}15{]}

A majority of the cases of MEN 2A in pregnancy reported so far where
surgery for MTC had to be undertaken during pregnancy were either
diagnosed for first time during pregnancy or presented with PCC crisis
leading to a diagnosis of MEN 2 and mandating the need for simultaneous
adrenalectomy and thyroidectomy. This case merits special attention not
only for highlighting the rarity of this syndrome during pregnancy but
also for the numerous challenges in management that were overcome to
deliver a successful outcome, which included a pandemic, an unplanned
pregnancy, second trimester surgery in a high-risk pregnancy, uneventful
COVID, pre-eclampsia at term culminating in an emergency cesarean
section!

This case posed a multitude of challenges in management which were
overcome by a well-coordinated multidisciplinary teamwork and the
effective utilization of teleconsultation services which proved to be
crucial in providing antenatal and postoperative services during such
testing times. It would be amiss to not recognize the courage of our
patient and the support provided by her family who braved such a
difficult pandemic to continuously remain in touch with us and also for
actively assisting us in decision making at several points of her
tumultuous course in hospital.

\textbf{LEARNING POINTS/TAKE HOME MESSAGES}

\begin{itemize}
\tightlist
\item
  Preconception and contraception counseling is very important in women
  of reproductive age group diagnosed with any medical disorder to avoid
  unplanned pregnancy. Optimization of condition before pregnancy is
  ideal.
\item
  Teleconsultation can be a very useful tool for managing high risk
  pregnancy if judiciously used in a pandemic like situation.
\item
  A well-coordinated interdisciplinary team approach can bring about
  successful outcome in pregnancy complicated by this rare syndrome.
\end{itemize}

FIGURE LEGENDS

Figure 1: Computed tomography (CT) image and corresponding fused PET
(positron emission tomography)/CT at the level of lower pole of thyroid
showing bilateral uptake (1A, B); Thyroid gland marked by asterisk

Figure S1: Coronal images Computed tomography (CT) image and
corresponding fused PET/CT of the suprarenal masses (2A, 2B).

Well-defined hetero-dense lesions with solid and cystic components noted
in both adrenals measuring \textasciitilde{}5.5 x 4.4 x 6.2 cm on right
side and \textasciitilde{}7.2 x 5.5 x 6.7 cm on left side with increased
radiotracer uptake in the solid component

Right adrenal gland marked by broad arrow, left adrenal gland marked by
narrow arrow

\textbf{Disclosure of interests:} None

\textbf{Contribution to authorship}

Aarti Chitkara: Conception and design of primary draft, acquisition of
data

Anubhuti Rana: Revision of manuscript and critical analysis of data

Setu Gupta: Drafting and critical analysis of Endocrine part of the
manuscript

Vidushi Kulshrestha: Critical revision and conceptualization of the
final draft of manuscript

ArunRaj Sreedharan Thankarajan: Imaging inputs and interpretation of the
nuclear imaging pertaining to the case

Vatsla Dadhwal: Critical revision of the final draft with significant
input in confirming the accuracy and integrity of the manuscript

\textbf{Patient consent} : A written consent was obtained from the
patient for publishing this case report as per institution protocol

\textbf{Funding} : None

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Steiner al, goodman ad, powers sr. Study of a kindred with
  pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and
  gushing's disease: multiple endocrine neoplasia, type 2. Medicine.
  1968 Sep 1;47(5):371-409.
\item
  Melvin KEW, Tashjian Jr AH, Miller HH 1972 Studies in familial
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\item
  Gagel RF, Tashjian Jr AH, Cummings T, Papathanasopoulos N, Kaplan MM,
  DeLellis RA, Wolfe HJ, Reichlin S. The clinical outcome of prospective
  screening for multiple endocrine neoplasia type 2a. New England
  Journal of Medicine. 1988 Feb 25;318(8):478-84.
\item
  Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B,
  Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, Modigliani E. Risk
  and penetrance of primary hyperparathyroidism in multiple endocrine
  neoplasia type 2A families with mutations at codon 634 of the RET
  proto-oncogene. The Journal of Clinical Endocrinology \& Metabolism.
  1998 Feb 1;83(2):487-91.
\item
  Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, Van
  Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ. The relationship
  between specific RET proto-oncogene mutations and disease phenotype in
  multiple endocrine neoplasia type 2: International RET Mutation
  Consortium analysis. Jama. 1996 Nov 20;276(19):1575-9.
\item
  Ponder BAJ 2001 Multiple endocrine neoplasia type 2. In: Scriver CR
  Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of
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\item
  Ghosh A, Nundy S, Mallick TK. How India is dealing with COVID-19
  pandemic. Sensors International. 2020 Jan 1;1:100021.
\item
  Gild M, Clifton-Bligh R, Robinson BG. Multiple Endocrine Neoplasia
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\item
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  during pregnancy. Journal of endocrinological investigation. 2002
  Jun;25(6):567-71.
\item
  Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman
  WA, Laurberg P, Lazarus JH, Mandel SJ, Peeters RP. 2017 Guidelines of
  the American Thyroid Association for the diagnosis and management of
  thyroid disease during pregnancy and the postpartum. Thyroid. 2017 Mar
  1;27(3):315-89.
\item
  Wells Jr SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N,
  Machens A, Moley JF, Pacini F, Raue F. Revised American Thyroid
  Association guidelines for the management of medullary thyroid
  carcinoma: the American Thyroid Association Guidelines Task Force on
  medullary thyroid carcinoma. Thyroid. 2015 Jun 1;25(6):567-610.
\item
  Silva OL, Titus-Dillon P, Becker KL, Snider RH, Moore CF. Increased
  serum calcitonin in pregnancy. Journal of the National Medical
  Association. 1981 Jul;73(7):649.
\item
  Tewari KS, Steiger RM, Lam ML, Rutgers JK, Berkson RA, DiSaia PJ.
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\item
  Sarathi V, Bandgar TR, Menon PS, Shah NS. Pheochromocytoma and
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  neoplasia-2A patient. Gynecological Endocrinology. 2011 Aug
  1;27(8):533-5.
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  Donatini G, Kraimps JL, Caillard C, Miralli\selectlanguage{ngerman}é E, Pierre F, De Calan L,
  Hamy A, Larin O, Tovkay O, Cherenko S. Pheochromocytoma diagnosed
  during pregnancy: lessons learned from a series of ten patients.
  Surgical endoscopy. 2018 Sep;32(9):3890-900.
\end{enumerate}

\textbf{Table S1:} Investigations for pheochromocytoma, MTC and
hyperparathyroidism as part of MEN 2A syndrome\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Component of MEN 2A}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Before Surgery}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Before Surgery}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{After Surgery}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{After Surgery}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Biochemical Findings}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Imaging}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Histopathology}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Imaging/ biochemical findings}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Pheochromocytoma} \emph{(Pre-pregnancy)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{24-hour Urine Adrenaline:} 81.74 ug/day (Normal \textless{}
20ug/day) \textbf{Noradrenaline:} 197.66 ug/day (Normal \textless{} 90
ug/day) \textbf{Urinary Free Cortisol:} 76ug/day (Normal \textless{}120
ug/day) \textbf{S. DHEAS:} 210 ug/dL\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\emph{CECT abdomen:} Bilateral enlargement of adrenal gland, with
heterogenous mass with areas of necrosis and cystic changes Size: 7.6 X
5.4 cm on right side and 5.5 X 4.4 cm on left side \emph{68-Ga-DOTANOC
Scan:} Uptake in the solid component of the lesions bilaterally\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bilateral pheochromocytoma; PASS-4\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Medullary Thyroid Carcinoma}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{S.Calcitonin} \emph{(Pre-pregnancy)}: 20 pg/ml (Normal
\textless{} 5 pg/ml) \textbf{S.Calcitonin} \emph{(At 22 weeks POG):}
42.1pg/ml\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{USG Neck:} \emph{(pre-pregnancy)} A TIRADS 5 nodule on right
lobe (5.8 x 3.7 mm). Two TIRADS 5 on left lobe of thyroid (8 x 5 mm);
\emph{USG Neck} \emph{(At 22 weeks POG, repeated before surgery)} Right
thyroid nodule (6.5 x 4.8 mm) and left thyroid nodule (6.2 x 5 mm)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Medullary thyroid carcinoma\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{USG Neck:} (\emph{At 32 weeks POG)}: No residual Lesion\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Hyper-parathyroidism}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{S. Calcium} \emph{(Pre-pregnancy):} 12.1mg/dL (Normal- 8.2-10.4
mg/dL \textbf{iPTH} \emph{(Pre-pregnancy):} 226 pg/ml (Normal
\textless{} 65 pg/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\emph{USG Neck:} \emph{(Pre-pregnancy)} A right inferior parathyroid
adenoma (9 x 5.2 mm); repeat imaging: 8 x 6 mm \emph{USG Abdomen:}
\emph{(Pre-pregnancy)} Bilateral nephrocalcinosis, right moderate
hydronephrosis\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Parathyroid adenoma\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{S. Calcium:} \emph{(At 24 weeks POG)} 9.1 mg/dL \textbf{iPTH:}
\emph{(At 24 weeks POG)} 8 pg/ml\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
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