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\begin{document}

\title{Case Report: Coexistence of Jacob Syndrome, congenital Adrenal
Hyperplasia, and Ambiguous Genitalia in a Male Infant}



\author[1]{Qaisar Ali Khan}%
\author[2]{Faiza Hadi}%
\author[3]{Amritpal Kooner}%
\author[4]{Amber Lee}%
\author[5]{Rahma Ahmed}%
\author[6]{Adithya Nadella}%
\author[7]{Harshawardhan Pande}%
\author[8]{Yaxel Levin-Carrion}%
\author[9]{Muhammad Afzal}%
\author[10]{Moses Alfaro}%
\affil[1]{Khyber Teaching Hospital, MTI KTH, Peshawar}%
\affil[2]{Mercer University School of Medicine}%
\affil[3]{Midwestern University Chicago College of Osteopathic Medicine}%
\affil[4]{Arkansas College of Osteopathic Medicine}%
\affil[5]{Kennesaw State University}%
\affil[6]{Nanjing Medical University}%
\affil[7]{St Louis University Department of Molecular Microbiology and Immunology}%
\affil[8]{Rutgers New Jersey Medical School}%
\affil[9]{St George's University True Blue Campus}%
\affil[10]{The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\textbf{Title Page}

Submission Category: Case Report

\textbf{Title:} Case Report: Coexistence of Jacob Syndrome, congenital
Adrenal Hyperplasia, and Ambiguous Genitalia in a Male Infant.

Qaisar Ali Khan\textsuperscript{1}; Faiza Amatul-Hadi,
BS\textsuperscript{2}; Amritpal Kooner, MA\textsuperscript{3}; Amber
Lee\textsuperscript{4}, Rahma Ahmed\textsuperscript{5,} Adithya
Nadella\textsuperscript{6} Harshawardhan~ Pande \textsuperscript{7} ,
Yaxel Levin- Carrion \textsuperscript{8},Muhammad
Afzal\textsuperscript{9},

Moses Alfaro, BSA\textsuperscript{10}

\emph{Affiliations:}\textbf{~}

\begin{enumerate}
\tightlist
\item
  Khyber Teaching Hospital MTI KTH, Peshawar, Pakistan
\item
  Mercer University School of Medicine, Macon, GA, USA
\item
  Chicago College of Osteopathic Medicine, Downers Grove, IL, USA
\item
  Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA
\item
  Kennesaw State University, Kennesaw, GA, USA
\item
  Nanjing Medical University, Nanjing, China
\item
  Saint Louis University, Missouri, USA
\item
  Rutgers New Jersy Medical School, New Jersy, USA
\item
  St. George's University School of Medicine, True Blue, Grenada
\item
  Long School of Medicine at the University of Texas Health Science
  Center San Antonio, San Antonio, TX, US
\end{enumerate}

\textbf{Corresponding author:} ~ ~ Muhammad Afzal

St. George's University School of Medicine, True Blue, Grenada

mafzal@sgu.edu

Manuscript Word Count: 2775

Number of Figures: 2

Number of Tables: 1

\textbf{Statement and Declarations}

The authors report no conflicts of interest.

No funding sources were utilized in the composition of this research.

\textbf{Consent:} A written informed consent was taken from the infant's
parents to publish this case or any accompanying images.

\textbf{Abstract:} A 5-month-old male infant was evaluated for ambiguous
genitalia. Examination revealed cryptorchidism, inguinal hernia, long
phallus, and grade 3 scrotal hypospadias. Serum 17- OH progesterone was
high and chromosomal analysis showed 47XYY/45XO. A diagnosis of Jacob
and CAH was made. The parents were counseled about the patient's
condition. He was given hydrocortisone and referred to the pediatric
surgeon for further management.

\textbf{Key clinical message:} Jacob syndrome and congenital adrenal
hyperplasia are separate entities but share common clinical features
such as ambiguous genitalia. Further studies are needed to conclude the
relationship between Jacob syndrome and congenital adrenal hyperplasia.

\textbf{Keywords:} congenital adrenal hyperplasia, Jacobs syndrome, XY
karyotype, virilization

\textbf{Introduction}

Congenital adrenal hyperplasia (CAH) describes a family of autosomal
recessive diseases caused by gene mutations encoding enzymes in the
cortisol biosynthesis pathway. The clinical and biochemical
manifestations of CAH are quite variable. The most common form of CAH,
making up more than 95\% of congenital adrenal hyperplasia cases,
results from 21-hydroxylase deficiency (21OHD), due to loss of function
mutation in CYP21A2. Classic CAH from 21OHD occurs in 1:10,000 to
1:20,000 live births with a female/male ratio of 2:1.
\textbf{{[}1{]}}Disease severity and phenotypic presentation vary
depending on the location and extent of gene mutations or deletions,
which lead to complex allelic variations.

Jacobs syndrome also known as 47, XYY syndrome, is caused by the
insertion of a male Y chromosome to 46, XY. It occurs in 0.1 \% of the
male population. Additionally, there are no specific clinical
manifestations in most boys with the XYY karyotype. Diagnosis of an XYY
karyotype is delayed (mean age at diagnosis is 17.1 years) and only 15\%
of patients are diagnosed with XYY syndrome. The karyotype 47, XYY is
relatively common, but its phenotypes are not well-understood. Patients
may vary greatly, ranging from no phenotype and relatively few
abnormalities to multi-systemic symptoms; for a specific symptom, the
severity can vary among individuals. \textbf{{[}2{]}}

XYY has also been sporadically reported in connection with several cases
of disorder of sex development (DSD). Ambiguous genitalia is the
condition commonly found in disorders of sex development (DSDs)
characterized by imperfect differentiation of external genitalia between
males and females. Sex Chromosome mosaicisms like 45 X0/46, XY, or 45
X/47 XYY have been considered major causes of ambiguous genitalia. Such
DSD phenotypes of XYY patients include micropenis, testicular dysplasia,
true-hermaphrodite, and complete sex reversal.\textbf{{[}3{]}}
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a
common cause of ambiguous genitalia in genotypically normal female
infants (46XX). Most males have no signs of CAH at birth. However, some
may present with hyperpigmentation and penile enlargement while those
with salt-wasting disease present early with hyponatremia and
hypovolemia. Males with non-salt-wasting disease present later with
signs of virilization. In rare forms, males are
under-masculinized.\textbf{{[}4{]}} This report highlights the rare case
of congenital adrenal hyperplasia coexisting with Jacobs syndrome
presenting as ambiguous genitalia.

\textbf{Case presentation:} A 5-month-old infant was brought to the
outpatient department of a tertiary care hospital for ambiguous
genitalia. The infant was born at 36 weeks of gestation to a 26-year-old
primigravida mother. The marriage was non-consanguineous and the
paternal and maternal ages were 30 and 26 years respectively. The
pregnancy was complicated due to delayed fertility for three years and
the mother revealed the use of herbal medicines during this period. The
infant had a birth weight of 3kg with an APGAR score of 9 at both 1 and
5 minutes.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

The infant had a height of 90 percentile, a weight of the 50 percentile
on the CDC chart, and attained age-appropriate milestones. On
examination of the genitalia, there was cryptorchidism with a long
phallus and grade 3 scrotal hypospadias as shown in Figure.1. The rest
of the clinical examination was unremarkable.

\textbf{Figure.1: Image presenting long phallus, inguinal swelling (A)
left-sided empty scrotum, and hypospadias (B).}

Ultrasound of the abdomen and pelvis was ordered that showed bilateral
undescended testis with left-sided inguinal hernia. Laboratory
investigations including hormonal levels were requested that revealed
increased serum 17-OH progesterone levels as shown in Table.1.

\textbf{Table} .\textbf{1: Hormonal Panel}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Investigation} & \textbf{Results} & \textbf{Normal
range}\tabularnewline
\midrule
\endhead
Serum cortisol (9 am) & 2.6 nmol/L & 4.4-25\tabularnewline
Serum testosterone & 4.9 nmol/L & 0.3-4.9\tabularnewline
17-OH progesterone & 28 nmol/L & 12-20\tabularnewline
Serum sodium & 138 mEq/L & 135-145\tabularnewline
Serum Potassium & 3.8 mmol/L & 3.5-5.0\tabularnewline
Serum chloride & 98 nmol/L & 90-110\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

A diagnosis of congenital adrenal hyperplasia was made and further
genetic study was performed to explore the potential genetic
abnormalities associated with the observed features. A total of 30 cells
were selected for chromosomal analysis and 21 showed 45X0 while the
other 9 showed 47XYY in a mosaic manner that confirmed the diagnosis of
Jacob syndrome as shown in Figure.2.

\textbf{Figure 2: Chromosomal analysis showing 47XYY/45XO}

The parents were counseled about the condition, its long-term
implication, and possible complications. The patient was started on
hydrocortisone 10mg/m\textsuperscript{2}/day in two divided doses for
four weeks and pediatric surgical and urological consultation was
arranged to address the patient's urogenital defects. Frequent follow-up
was suggested to regularly monitor the patient's hormones, growth, and
development.

\textbf{Discussion~}

Congenital adrenal hyperplasia (CAH) is a group of inherited disorders
that are present at birth where the adrenal glands are hyperplastic,
most commonly resulting from mutations or deletions of CYP21A. In CAH,
the body is missing an enzyme that stimulates the adrenal gland to
release cortisol. Disease severity and phenotypic presentation vary
depending on the location and extent of gene mutations or deletions,
which lead to complex allelic variations. Almost 300 CYP21A2 mutations
have been identified, making genotyping these individuals a cumbersome
undertaking. CAH can be seen as a continuum from salt wasting to mild
forms but is divided into two categories for convenience: classical
approximately 67\% (``salt-losing,'' severe, ex-congenital), and
nonclassical approximately 33\% (``non-salt-losing'' or
``simple-virilizing,'' less severe, formerly known as late-onset or
cryptic) according to the degree of aldosterone deficiency~ Patients
with classic CAH may present as simple virilizing CAH or salt-wasting
CAH and are usually diagnosed in infancy while patients with
non-classical~ CAH may be asymptomatic or present with a milder form of
virilization postnatally. \textbf{{[}5{]}} CYP21, found on chromosome
6p, near the human leukocyte antigen gene cluster, is the gene for
adrenal 21-hydroxylase. Specific mutations may be linked to a degree of
enzymatic dysfunction and the clinical manifestation of 21-hydroxylase
insufficiency. Minor mutations on both alleles of the 21-hydroxylase
gene are found in patients with non-classic forms \textbf{{[}6{]}} A
retrospective cohort study conducted by Gidl\selectlanguage{ngerman}öf et al. in Sweden found
the CYP21A2 genotype in 81\% of the patients, reflecting improved
diagnostic usage of genetic studies. \textbf{{[}7{]}} The infant we are
reporting was diagnosed solely based on clinical findings and laboratory
values. Due to financial constraints and resource availability, genetic
studies could not be conducted in our case.

It is shown that up to 29.3\% of CAH patients had adrenal tumors.
Abdominal ultrasound is the modality of choice for small-sized pediatric
patients due to the lack of ionizing radiation, lower cost than
cross-sectional imaging, and extensive availability. \textbf{{[}8{]}} In
our situation, the ultrasound of the infant resulted in the adrenal
glands being normal, ruling out the likelihood of an adrenal tumor.

Symptoms of Jacobs syndrome may be quite vague during childhood, and for
this reason, most children go undiagnosed. However, Men with Jacobs
syndrome who do display symptoms are most likely to exhibit tall stature
and macrocephaly. Developmental delays and behavioral issues have been
noted, as well as atonia, clinodactyly (medial curvature of a digit,
i.e., 5th finger toward the 4th), and hypertelorism. The incidence of
asthma and autism spectrum disorder also appears to be increased in
these individuals. \textbf{{[}9{]}} other conditions such as Marfan
syndrome and Sotos syndrome should be ruled out, in contrast to Jacobs
syndrome, Marfan syndrome often presents with cardiac abnormalities such
as aortic root dilatation and mitral valve prolapse. Sotos syndrome,
also known as cerebral gigantism, is a rare genetic condition caused by
a mutation in the NSD1 gene. Hallmark features include excessive growth
during childhood, macrocephaly, learning disabilities, hypotonia, and
seizure disorders. \textbf{{[}10{]}} Our patient had none of them.

Patients with Jacobs syndrome have been found to have an increased
incidence of certain diseases. These include asthma, seizure disorders,
and tremors. Some 47, XYY patients have been noted to have genitourinary
abnormalities such as microphallus, hypoplastic scrotum, cryptorchidism,
and hypospadias. These patients are also at an increased risk for
learning disabilities, ADHD, autism spectrum disorder, and speech
difficulties. \textbf{{[}11{]}}

The diagnosis of both CAH and Jacobs syndrome can be done prenatally
with amniocentesis or chorionic villus sampling, and treatment involves
dexamethasone administered at or before 10 weeks of gestation. A study
conducted by Carlson et al. found that prenatal diagnosis and therapy of
21-hydroxylase deficiency is safe and effective in lowering or
eliminating virilization in the affected female, sparing the newborn
female the repercussions of genital ambiguity, sex misassignment, and
gender confusion. \textbf{{[}12{]}} However, in our case, the mother did
not undergo routine antenatal visits during the pregnancy leading to the
failure of antenatal diagnosis of CAH as well as Jacob syndrome.

There is no treatment for XYY syndrome. The treatment option is
generally only supportive, with attention given to the comorbidities of
the patient. While medication cannot treat XYY syndrome, some
medications can be used to treat conditions related to the syndrome. A
person with XYY syndrome can get help with any learning or developmental
delays through speech therapy, occupational therapy, or other
assistance. Therapy can also help with ADD/ADHD, social interactions,
and other behavioral problems. While The treatment for CAH is based on
replacing normal glucocorticoid and mineralocorticoid needs, as well as
psychological support \textbf{{[}13,14{]}} The patient is currently
receiving hydrocortisone. The parents of the infant were counseled about
the need for genital surgery and psychological support.

\textbf{Conclusion}

This rare case highlights the co-existence of CAH and Jacob syndrome
(47, XYY Syndrome) that leads to ambiguous genitalia and various
urogenital abnormalities and underscores a stepwise diagnostic approach
in patients with atypical presentation. A multidisciplinary approach
including endocrinology, surgery, and genetics is necessary for the
proper management of complexities associated with the condition. Further
research is needed to find the association between CAH and Jacob
syndrome in patients with ambiguous genitalia.

\textbf{Acknowledgments}

None

\textbf{Conflict of interest~}

The authors report no conflict of interest.

\textbf{Funding~}

No funding sources were utilized in the composition of the research.

\textbf{Author's contributions~}

Qaisar Ali Khan was responsible for data collection and acquisition of
data. Amber Lee, Amritpal Kooner, Rahma Ahmed, Yaxel Levin-Carrion,
Moses Alfaro , Muhammad Afzal, Adithya Nadella, and Harshawardhan Pande
performed the literature review and wrote the manuscript. Qaisar Ali
Khan and Faiza Amatul Hadi reviewed and critically revised the
manuscript. All authors have approved the final manuscript.

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