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\begin{document}

\title{A Brother and Sister with the Same Karyotype: Case Report of Two
Siblings with Partial 3p Duplication and Partial 9p Deletion and Sex
Reversal}



\author[1]{Susan Cordes Selby}%
\author[2]{Aiko Iwata-Otsubo}%
\author[2]{Paula Delk}%
\author[2]{Todd Nebesio}%
\author[2]{Anisha Gohil}%
\author[2]{Wilfredo Martinez}%
\author[2]{Peggy Matlock}%
\author[2]{Gail Vance}%
\affil[1]{Community Hospitals of Indianapolis}%
\affil[2]{Indiana University School of Medicine}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Duplications of 3p and deletions of 9p occurring separately are well
described; however, there are few reports of individuals with unbalanced
translocations resulting in both of these chromosomal abnormalities. We
report two siblings with the same unbalanced male karyotype and sex
reversal.%
\end{abstract}%



\sloppy


A Brother and Sister with the Same Karyotype: Case Report of Two
Siblings with Partial 3p Duplication and Partial 9p Deletion and Sex
Reversal

Susan Cordes Selby\textsuperscript{1}, Aiko
Iwata-Otsubo\textsuperscript{2}, Paula Delk\textsuperscript{2}, Todd D.
Nebesio\textsuperscript{3}, Anisha Gohil\textsuperscript{3}, Peggy
Matlock\textsuperscript{2}, Wilfredo Torres-Martinez\textsuperscript{2},
Gail H. Vance\textsuperscript{2}

\textsuperscript{1} Community Health Network, Maternal-Fetal Medicine,
Indianapolis, IN

\textsuperscript{2}Department of Medical and Molecular Genetics, Indiana
University School of Medicine, Indianapolis, IN

\textsuperscript{3}Division of Pediatric Endocrinology/Diabetology,
Department of Pediatrics, Indiana University School of Medicine,
Indianapolis, IN

Running Title: Siblings with 46,XY,der(9)t(3;9)(p25.1;p24.3)

Correspondence to: Gail H. Vance, Department of Medical and Molecular
Genetics, Indiana University School of Medicine, 975 W Walnut Street
IB-350, Indianapolis, IN 46202-5251. Phone: 317-278-0172. Fax:
317-278-1616. Email: ghvance@iu.edu

\textbf{ABSTRACT}

Duplications of 3p and deletions of 9p occurring separately are well
described; however, there are few reports of individuals with unbalanced
translocations resulting in both of these chromosomal abnormalities
together. Here we report two siblings with the same unbalanced male
karyotype, with a duplication of distal 3p and a deletion of distal 9p,
due to adjacent segregation of a balanced reciprocal translocation
inherited from their father. Although the siblings have the same
karyotype of 46,XY,der(9)t(3;9)(p25.1;p24.3)pat, they demonstrate
different phenotypes, particularly in sex development. This sibling pair
further delineates cases with unbalanced translocations and disorders of
sex development.

\textbf{KEY WORDS}

3p duplication; 9p deletion; disorders of sex development; \emph{DMRT1}

\textbf{KEY CLINICAL MESSAGE}

Two siblings with the same male unbalanced karyotype with sex reversal
in the female.

\textbf{INTRODUCTION}

There have been few patients reported with both partial duplication of
3p and partial deletion of 9p due to an unbalanced translocation with
variable breakpoints (Figure S1) (Fryns et al., 1986; \selectlanguage{ngerman}Õunap et al.,
2004; Witters et al., 2004). Two prior reports of individuals with
similar unbalanced translocations to the patients in this report,
suggested that the clinical features overlap with those of individuals
with isolated 3p duplications and 9p deletions; however, they are
generally milder than expected for the degree of imbalance (Game et
al.,1990; McClure et al., 1996) .

Patients with 3p duplications have variable clinical features that
include intellectual disability, hypotonia, short stature, heart defects
and facial features such as brachycephaly, microcephaly, square face,
hypertelorism, wide and depressed nasal bridge, short nose, full cheeks,
and cleft lip with and without cleft palate. (Bittel et al., 2006;
Natera-de Benito et al., 2014; Smeets et al., 2001).

Clinical features of the 9p deletion syndrome, (OMIM \#158170), include
developmental and psychomotor delay, hypotonia, widely spaced nipples,
and dysmorphic facial features, such as midface hypoplasia, short
palpebral fissures, hypertelorism, depressed nasal bridge and
micrognathia (Alfi et al., 1973; Hauge et al., 2008; Huret et al., 1988;
Swinkels et al., 2008). A significant number of patients with a distal
9p deletion with a male karyotype exhibit disorders of sex development
(DSD) (Barbaro et al., 2009; Õunap et al., 2004).

Here, we report a brother and sister with the same male karyotype with
an unbalanced translocation resulting in partial duplication of 3p and
distal deletion of 9p. Both patients' clinical features include those
seen in 3p duplication and 9p deletion, including abnormal sex
development.

\textbf{CLINICAL REPORTS}

\textbf{Patient 1}

Patient 1 was born at 38 weeks gestation by repeat Cesarean section to a
33-year-old G2P1001 mother. Prenatal ultrasound detected a Dandy-Walker
malformation, confirmed after birth with brain MRI. The remainder of the
pregnancy was unremarkable. The family history was remarkable for a
sister (patient 2) with an atrial septal defect (ASD) and clubfeet. The
remainder of the family history was negative for birth defects,
intellectual disability, and recurrent miscarriages. The mother and
father are second cousins (their mothers are first cousins).

The patient's birth weight was 3.78 kg
(69\textsuperscript{th}percentile), length was 54.0 cm
(93\textsuperscript{rd} percentile), and Apgar scores were 8 and 9 at 1
and 5 minutes, respectively. He had neonatal hypoglycemia, which
resolved spontaneously within the first day of life, and feeding
difficulties, which resolved by 6 months of age. A patent foramen ovale
was identified.

At birth, the patient had ambiguous genitalia with a bifid scrotum.
Specifically, he had a penoscrotal transposition with buried penis and
prominent suprapubic fat pad. He also had ventral chordee, left-sided
hydrocele, and a left inguinal hernia. The patient had a low luteinizing
hormone (LH) and lower limits of normal follicle-stimulating hormone
(FSH) in the newborn period. Testosterone and dihydrotestosterone levels
were normal for age, but anti-Mullerian hormone was low for newborn
males, suggesting normal Leydig cell function but abnormal Sertoli cell
function. A renal ultrasound showed normal appearing kidneys bilaterally
with no evidence of hydronephrosis. At 7 months of age, the patient had
a penoplasty, scrotoplasty and repair of the left inguinal hernia and
hydrocele.

The patient had both developmental and speech delay, He sat alone at
approximately 5 months, crawled at 11 months, and was not walking
independently at 16 months of age. Growth parameters at 16 months of age
were 11.4 kg (53\textsuperscript{rd} percentile) for weight, 78.6 cm
(29\textsuperscript{th} percentile) for length, and an OFC of 49 cm
(87\textsuperscript{th} percentile). Mildly dysmorphic features observed
included short palpebral fissures with hypertelorism, cupped ears with
overfolded helices, short nose, a smooth philtrum, full cheeks, and
micrognathia. (Figure 1a). Other features noted were displaced nipples,
tapered fingers, edema of the feet, and loose skin.

At age 9 years, he underwent an adenoidectomy and turbinate
cauterization due to concerns for apnea. His growth parameters for
height, weight and head circumference were at the
75\textsuperscript{th}-90\textsuperscript{th} percentile. He had
moderate expressive and receptive language delays and received speech
intervention, occupational, music, physical, and recreational therapies.
He was diagnosed with ADHD, and is homeschooled, working at a 3rd grade
level. At age 10 years 11 months, he is prepubescent. A testicular
ultrasound revealed healthy appearing bilateral testes located within
the scrotum without mass or concerning features. His gender identity
remains male.

G-banded chromosome analysis, performed at birth, identified additional
unknown material on 9p. Parental blood studies demonstrated that the
patient's father had a balanced reciprocal translocation between 3p and
9p written as 46,XY,t(3;9)(p25.1;p24.3). Based on paternal results, the
patient's karyotype was revised to 46,XY,der(9)t(3;9)(p25.1;p24.3)pat,
resulting in partial 3p duplication and partial 9p deletion.

Chromosomal microarray analysis (CMA) identified a duplication at
3p26.3p25.1, approximately 13.5 Mb in size involving 55 OMIM genes
(chr3:61,891-13,562,132, hg19 coordinates) and a deletion at 9p24.3,
approximately 1.17 Mb in size involving 5 OMIM genes
(chr9:203,861-1,373,611, hg19 coordinates). Also identified were
segments of copy-neutral absence of heterozygosity (AOH) across multiple
chromosomes encompassing around 2.2\% of the genome (Figure S2).

\textbf{Patient 2}

Patient 2 (sister to patient 1) was born at term by Cesarean section due
to large size and posterior positioning. The pregnancy was without
complications. Birth weight was 3.94 kg
(87\textsuperscript{th}percentile) and birth length was 48.9 cm
(43\textsuperscript{rd}percentile). Hypoglycemia developed shortly after
birth, which resolved spontaneously. She had bilateral talipes
equinovarus and a moderate-sized ASD noted by echocardiogram.

A chromosome study of Patient 2 demonstrated the same karyotype as her
brother, 46,XY,der(9)t(3;9)(p25.1;p24.3)pat. However, she had
normal-appearing female external genitalia. A renal ultrasound was
normal, and a pelvic ultrasound initially appeared normal with both
ovaries and a uterus present. Gonadotropins measured at 2 years 8 months
demonstrated her LH was normal but FSH was markedly elevated, suggesting
gonadal dysgenesis and primary ovarian dysfunction. Laparoscopy showed a
normal uterus and Fallopian tubes. The ovaries appeared normal except
for a right cystic structure. The patient had a bilateral gonadectomy.
Pathology reports of the left gonad revealed a streak testis containing
a gonadoblastoma while the right gonad was an ovotestis.

The patient had developmental delays, especially with gross motor and
language skills. She walked at 20 months and said her first words at 18
months. At 3 years 2 months, her vocabulary consisted of reportedly more
than 100 single words and she was able to use two-word phrases.

The patient's growth parameters at 3 years 5 months of age were 15.4 kg
(64\textsuperscript{th} centile) for weight, 98 cm
(56\textsuperscript{th} centile) for height, and she had an OFC of 51.2
cm (80\textsuperscript{th} centile). At age 11 years, her growth
parameters were at
75\textsuperscript{th}-90\textsuperscript{th}percentiles for height,
weight and head circumference. Dysmorphic features included
brachycephaly, broad forehead, short nasal bridge, and hypoplastic ala
nasi. Percutaneous closure of her ASD was performed and she has remained
asymptomatic. On endocrine evaluation at age 11 year 7 months, her
breasts were at Tanner stage I and pubic hair was Tanner stage III. She
began treatment for hypergonadotropic hypogonadism with an estradiol
patch at 12.5 mcg twice weekly. Her bone age was concordant with her
chronological age of between 10 and 11 years. An exam at age 13 years 8
months, noted Tanner stage III breasts and Tanner stage IV pubic hair.
She has not yet had menarche. Her gender identity remains female.

Developmentally, the patient was functioning with moderate cognitive
delays and severe language delay. She was receiving speech,
occupational, and recreational therapies. She has been homeschooled and
is performing near the 4\textsuperscript{th} grade level.

Similarly, a CMA showed a duplication at 3p26.3p25.1, approximately
13.46 Mb in size involving 55 OMIM genes (chr3:61,891-13,562,132, hg19
coordinates) and a deletion at 9p24.3, approximately 1.17 Mb in size
involving 5 OMIM genes (chr9:203,861-1,373,611, hg19 coordinates; Figure
1c). The microarray also identified segments of copy-neutral AOH across
multiple chromosomes encompassing around 3.8\% of the genome (Figure
S2).

\textbf{MATERIALS AND METHODS}

High-resolution chromosome analysis was performed on 20 metaphases on
PHA-stimulated cultured lymphocytes using the standard GTG (G-banding
using trypsin and Giemsa) banding protocol. CMA analysis was performed
on genomic DNA extracted from peripheral blood using the Applied
Biosystems CytoScan HD array platform (ThermoFisher Scientific,
Carlsbad, CA) consisting of 1,953,246 unique non-polymorphic copy-number
probes and 743,304 single nucleotide polymorphism probes spanning the
whole genome. CytoScan array CEL files were processed and visualized
with the Chromosome Analysis Suite (ChAS) 3.3 version software
(ThermoFisher Scientific, Carlsbad, CA) The copy number variants (CNVs)
were analyzed and reported using the NCBI human genome build 37.1
(GRCh37/hg19).

\textbf{DISCUSSION}

In this report, we present phenotypically male and female siblings each
with the same male karyotype with partial 3p duplication and partial 9p
deletion. Their clinical features overlap those associated with 3p
duplication and 9p deletion (Table S1). The duplicated 3p and deleted 9p
regions are smaller in our patients compared to the common sizes
associated with patients reported in the literature, which could account
for the milder phenotype in our patients.

The 9p deletion syndrome is associated with DSD. Patients with a distal
9p deletion and a male karyotype, show a wide spectrum of abnormal sex
development ranging from females with complete gonadal dysgenesis to
males with hypospadias. The critical region for complete gonadal
dysgenesis has been localized to the 9p24.3, extending from
the\emph{DMRT} genes to the telomere (Barbaro et al., 2009; Guioli et
al., 1998; Veitia et al., 1997) This region is separate from the 9p
deletion syndrome critical region (9p22.3-9p23) (Flejter et al., 1998;
Veitia et al., 1997). The \emph{DMRT} genes (\emph{DMRT1} , \emph{DMRT2}
, and\emph{DMRT3} ) located at 9p24.3 are considered as gene candidates
for gonadal dysgenesis (Muroya et al., 2000). These genes encode for
proteins with a DM (doublesex/MAB-3) domain, a zinc-finger-like DNA
binding, and are involved in downstream pathways of sex determination
(Barbaro et al., 2009). In mice, \emph{Dmrt1} is expressed in both germ
cells and Sertoli cells of the testis, and has been shown to be
essential to maintain testis determination (Raymond, 2000). Recent
studies in humans support that haploinsufficiency of
\emph{DMRT1,}associated with 9p deletions, is the most likely
explanation of DSD. Macdonald et al. (2018) used a novel approach to
repress \emph{DMRT1} in the tissue of human fetal testes, and showed
\emph{DMRT1} repression induces testicular dysgenesis. Furthermore, a
recent exome study identified a missense mutation in \emph{DMRT1} in a
patient with XY sex reversal (Murphy et al., 2015) further supporting
that \emph{DMRT1} is a candidate gene for XY sex reversal.

It has been shown that haploinsufficiency for \emph{DMRT1} results in
gonadal dysgenesis and DSD with variable penetrance and expressivity
(Quinonez et al., 2013). A review of 88 cases of monosomy 9p with a male
karyotype revealed that \textasciitilde{}80\% (72/88) had genital
abnormalities and/or complete gonadal dysgenesis, while
\textasciitilde{}20\% of them had no genital abnormalities. The
underlying mechanism of this variability has been unclear. Since a large
percentage of 46,XY patients with 9p deletions that had DSD harbored a
secondary copy number variation (CNV), the authors hypothesized that
abnormal sex development may be due to the presence of a second-hit (CNV
or other molecular mechanism) in addition to
\emph{DMRT1}haploinsufficiency. In our study, we did not detect
significant CNVs however, regions of AOH were detected with the regions
of AOH in patient 2 being larger (3.78\% of the entire genome including
62 Mb AOH on chromosome 7) than in patient 1 (2.22\% of the entire
genome; Figure S2). It may be possible that a homozygous state of a gene
or genes in the AOH regions in patient 2 served as a second hit,
accounting for her sex reversal phenotype. Alternatively, it may be
possible that additional small CNVs or other genetic changes
undetectable by CMA account for the difference in sex development
between the two patients.

In conclusion, the two patients reported here add to the study of
individuals with partial 3p duplication and 9p deletion. Of reported
cases, only two have had 46,XY and sex reversal (Fryns et al., 1986;
Witters et al., 2004). Our two patients are also of interest as they are
a brother and sister with the same genotype defined by karyotype and
CMA, but their phenotypes, specifically in regards to sex development
and gender identity, are different.

\textbf{ACKNOWLEDGEMENTS}

We thank the family for their cooperation with this study.

\textbf{DATA AVAILABILITY}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{AUTHOR CONTRIBUTIONS}

Clinical Evaluation SCS, PD, TDN, AG, WTM; Data Analysis AIO, PM, GHV;
SCS, AIO and GHV prepared the manuscript; all authors reviewed and
contributed to the drafts and approved the final manuscript.

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\textbf{FIGURE LEGENDS}

\textbf{Figure 1} - Pictures and CMA results of the two patients

Frontal and lateral views of the patient 1 at the age of 9 months
showing a square face, hypertelorism, short palpebral fissures, short
nose, full cheeks, cupped ears, smooth philtrum, and micrognathia. (b)
Frontal and lateral views of the patient 2 at the age of 2 years 10
months showing hypertelorism, epicanthal folds, smooth philtrum, and
depressed nasal bridge. (c) CMA results of patient 1 and patient 2. Both
patients have the same deletion on chromosome 9p and duplication on
chromosome 3p. Patient 2 has additional 85 kb- and 42 kb-deletions with
no genes present in these regions. These CNVs are considered
insignificant.

\textbf{Figure S1} -Schematic representation of 3p duplications (a) and
9p deletions (b) in this study and previous reported cases.

\textbf{Figure S2} -AOH regions in patient 1 and patient 2 detected by
CMA analysis are shown as purple box. Patient 2 has larger AOH region
(3.78\% of the entire genome) than patient 1 (2.22\% of the entire
genome), including 62 Mb AOH region on chromosome 7.

\textbf{A Brother and Sister with the Same Karyotype: Case Report of Two
Siblings with Partial 3p Duplication and Partial 9p Deletion and Sex
Reversal}

Susan Cordes Selby\textsuperscript{1}, Aiko
Iwata-Otsubo\textsuperscript{2}, Paula Delk\textsuperscript{2}, Todd D.
Nebesio\textsuperscript{3}, Anisha Gohil\textsuperscript{3}, Peggy
Matlock\textsuperscript{2}, Wilfredo Torres-Martinez\textsuperscript{2},
Gail H. Vance\textsuperscript{2}

\textsuperscript{1} Community Health Network, Maternal-Fetal Medicine,
Indianapolis, IN

\textsuperscript{2}Department of Medical and Molecular Genetics, Indiana
University School of Medicine, Indianapolis, IN

\textsuperscript{3}Division of Pediatric Endocrinology/Diabetology,
Department of Pediatrics, Indiana University School of Medicine,
Indianapolis, IN

Gail H. Vance, Department of Medical and Molecular Genetics, Indiana
University School of Medicine, 975 W Walnut Street IB-350, Indianapolis,
IN 46202-5251. Phone: 317-278-0172. Fax: 317-278-1616. Email:
ghvance@iu.edu\selectlanguage{english}
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