Case Report
A Novel Presentation of Proopiomelanocortin (POMC) Deficiency
Cohen L*, Feuer A and Bergstrom K
Department of Pediatrics, Weill Cornell Medical College, USA
*Corresponding author: Lilian Cohen, Department of PediatricsDivision of Medical Genetics, Weill Cornell Medical College, 505 East 70th St, 3rd Floor Box 128, NY 1002, New York, USA
Published: 15 Jun, 2016
Cite this article as: Cohen L, Feuer A, Bergstrom
K. A Novel Presentation of
Proopiomelanocortin (POMC)
Deficiency. Ann Clin Case Rep. 2016;
1: 1021.
Abstract
Proopiomelanocortin (POMC) deficiency is a rare form of monogenic obesity which typically presents in infancy with hypoglycemic seizures and reduced cutaneous pigmentation. Over time, these patients develop morbid obesity along with multiple endocrinopathies including adrenal insufficiency, hypogonadism, hypothyroidism and growth hormone deficiency. Here, we describe an 11 year old male with adrenal insufficiency, seizure disorder, morbid obesity, and intellectual disability of unknown etiology recently confirmed to have POMC deficiency based on whole-exome sequencing (WES). This case highlights the advances in molecular genetic testing and opportunities for diagnosis in patients with complex medical histories or atypical clinical manifestations.
Introduction
Proopiomelanocortin (POMC) deficiency, a rare form of monogenic obesity, is characterized
by early-onset marked obesity, adrenal insufficiency and reduced cutaneous pigmentation. In the
first months of life, most children with POMC deficiency experience hyperphagia, cholestasis,
and adrenal insufficiency. POMC deficient patients commonly present with severe hypoglycemia
and seizures in the neonatal period as well as hyperbilirubinemia. Hyperphagia is apparent soon
after birth leading to rapid weight gain throughout the first year of life and severe childhood
obesity. Central hypothyroidism, adult-onset growth hormone deficiency and hypogonadotropic
hypogonadism have also been observed in POMC deficient patients [1].
POMC, the polypeptide precursor of several biologically active peptides, is cleaved by a series
of prohormone convertases to produce adrenocorticotropic hormone (ACTH) and the three
melanocyte-stimulating hormones (MSH): alpha, beta and gamma. These hormones are the
endogenous ligands of the melanocortin family of receptors (MCR) of which there are five known
members. The hair and skin manifestations, adrenal insufficiency and obesity are caused by lack of
activation of the MC1, MC2, and MC4 receptors respectively [2]. POMC deficiency may be initially
diagnosed clinically due to the unique constellation of symptoms and then confirmed by mutation
analysis.
Here we report a case of POMC deficiency confirmed via whole exome sequencing (WES) with
a unique presentation, including lack of neonatal hypoglycemia and red hair, as well novel clinical
manifestations including duodenal perforation, a seizure disorder not related to hypoglycemia,
severe developmental delay and autism.
Case Presentation
An 11 year old male with a history of adrenal insufficiency, seizure disorder, acquired primary
hypothyroidism and morbid obesity was referred for genetic evaluation of profound developmental
delay, seizures and continued rapid weight gain. He was born at 40 weeks gestation via spontaneous
vaginal delivery to a 28 year-old mother with A1 (diet-controlled) gestational diabetes and a 30
year-old non-consanguineous father, both of Hispanic ethnicity. His birth weight was average
for gestational age at 3153 grams. After delivery, he was admitted to the neonatal intensive care
unit (NICU) for seizures secondary to presumed hypoxic ischemic encephalopathy. He had
no documented hypoglycemia during this period. He remained hospitalized for two months
for hyperbilirubinemia, intra-hepatic cholestasis and persistent seizures. He was subsequently
diagnosed with a seizure disorder and progressive intra-hepatic cholestasis and was discharged to
home on medical therapy. He was then readmitted at 5 months of age with spontaneous duodenal
perforation and septic shock. During this admission, the patient had refractory hypotension and
a low morning cortisol level of 1.7 ug/dL. He was started on hydrocortisone therapy which was weaned after recovery from his acute illness. At 7 months of age, physiologic dosing of hydrocortisone was initiated after cosyntropin
stimulation testing revealed undetectable baseline cortisol and ACTH
levels and a low stimulated cortisol level of 1.5ug/dL. The results of his
endocrine testing are listed in Table 1.
The patient was noted to have rapid weight gain between 8
to 12 months and his weight was >99th percentile by 21 months of
age. He continued to have exponential weight gain despite dietary
modification and increased physical activity. He was started on
levothyroxine supplementation at 18 months of age for persistently
elevated thyroid stimulating hormone (TSH) levels in the context of
negative thyroid antibodies. He has profound developmental delay
and autism and continues to have seizures twice monthly despite
antiepileptic medications. There has been no reported hypoglycemia
during any of his seizures to date. His linear growth rate has been
appropriate throughout childhood. He was recently referred to our
genetics clinic for a new consultation by the neurologist for genetic
testing related to his seizures and autism. On exam, his height, weight
and body mass index were: 151.9 cm (72%, Z = 0.58), 68.6 kg (99%,
Z = 2.25), and 29.23 Kg/m2
(99%, Z = 2.25) respectively. He was a
well-appearing, non-dysmorphic male with tan skin and dark brown
hair. He was in early puberty with Tanner II pubic hair and 4cc testes
bilaterally. He had marked acanthosis nigricans of the posterior
neck, axillae and groin. Molecular genetic studies were obtained with
informed consent from the patient's mother. Genomic DNA was
extracted from peripheral blood samples.
Table 1
Results
A karyotype was performed on a sample of this patient's blood to
rule out the presence of chromosomal aneuploidies and unbalanced
translocations. This result was normal, 46, XY. Whole genome
single nucleotide polymorphism (SNP) microarray analysis was
performed to rule out the presence of chromosomal microdeletions
and microduplications greater or equal to 50 kilo bases in size. No
abnormalities were detected via microarray; however, this patient
was noted to have areas of homozygosity, consistent with a family
history of consanguinity and increasing the risk for the presence of
an autosomal recessive disorder in the patient. Fragile X syndrome
PCR analysis and Prader-Willi syndrome methylation studies were
within normal limits. Metabolic screening studies including plasma
amino acid levels, urine organic acids, urine orotic acids, and plasma
ammonia levels, were performed to assess the likelihood for an
underlying inborn error of metabolism. While the patient's initial
plasma amino acid levels were suggestive of hyperornithinemia, his
follow-up additional metabolic studies were within normal limits. His
lipid profile showed a low HDL level, otherwise within normal limits.
Clinical whole exome sequencing was then performed at Ambry
Genetics via their ExomeNextTM assay in an attempt to identify an
underlying genetic cause for the patient's phenotype, given his
previous uninformative workup. A blood sample from the patient's
biological mother was submitted to aid in the analysis. While testing a
trio, typically the proband and two first degree relatives, increases the
likelihood of a definitive result, the biological father was unavailable
to provide a sample for analysis. Testing revealed homozygous frame
shift deleterious mutations in this patient's proopiomelanocortin
(POMC) genes, at chromosomal location 2p23.3. The mutation,
c.20_21ins25, is a frameshift mutation altering the translation of the
proopiomelanocortin protein. This mutation is classified as known
disease-causing/pathogenic and is consistent with a diagnosis of
POMC deficiency. The patient's mother was identified as a carrier of
a heterozygous POMC gene c.20_21ins25 mutation. It is suspected
that this patient's father is also a carrier of the same mutation, though
confirmation was not possible.
Discussion
POMC deficiency has been previously described as a syndrome
of central adrenal insufficiency, obesity and characteristic hair and
skin pigmentation which may be associated with childhood and
adolescence-onset central hypothyroidism and hypogonadotropic
hypogonadism. This case illustrates a unique instance of POMC
deficiency in which the patient did not have hypoglycemia documented
in the neonatal period or external abnormalities in hair and skin
pigmentation. Additionally, his seizure disorder and developmental
delay is thought to be secondary to perinatal anoxic brain injury and
not from hypoglycemia secondary to congenital ACTH deficiency
as has been previously described in cases of POMC deficiency [3-
6]. Instead, his adrenal insufficiency was diagnosed at 5 months of
age during evaluation for refractory hypotension concomitant with
sepsis. The patient's lack of characteristic neonatal hypoglycemia
and red hair/fair skin coupled with his history of seizure disorder
and developmental delay likely obscured his diagnosis and led to a
considerable delay in obtaining confirmatory genetic testing.
In this case study, we successfully confirmed the genetic diagnosis
in a patient with POMC deficiency after 11 years of extensive
inpatient hospitalizations and outpatient care. Given his history
of developmental delays/intellectual disabilities (ID) and seizures,
this patient went through an extensive series of testing without
informative answers [7,8]. The lack of major facial dysmorphisms,
absence of congenital anomalies, along with an unclear etiology of
early adrenal insufficiency made clinical diagnosis difficult until
WES identified this single frameshift mutation. In our patient as
well as those in recent studies, this case highlights how a definitive
diagnosis of a genetic disorder can provide valuable information
about prognosis, anticipatory guidance, and recurrence risk [9]. In
children, this knowledge becomes increasingly important in terms of
intervention, medical therapy and preventative health care. Accurate
diagnosis for patients with POMC deficiency can allow for timely
surveillance and management of hypoglycemia as well as treatment of
ACTH, TSH, GH, LH, and FSH deficiencies. Unfortunately, the true
prevalence of POMC deficiency remains unknown as these syndrome
likely remains under diagnosed [1]. With improving our knowledge
of genetic mechanisms causing neonatal hypoglycemia or metabolic
disorders in early childhood, further studies of earlier treatment
approaches can be tailored for the individual patient to maximize
neurodevelopmental outcomes
Advances in molecular testing are becoming increasingly available
in the clinical setting. There are over 340 genes just associated with
epilepsy, many of which have overlapping phenotypic features [7].
The improvements in sequencing technology and bioinformatics,
turnaround time as a commercial service, and better insurance
coverage for testing have allowed patients and family to access this
diagnostic tool. WES is becoming more cost effective compared to
traditional protocols involving serial genetic testing, particularly
for conditions characterized by genetic heterogeneity [9]. There are
limitations to whole exome sequencing which may be overlooked by
nongeneticists, particularly when receiving a negative WES result.
Mutations and/or causal variants may be in an exon of a gene that is
poorly covered in the assay. Disease causing variant(s) may also be in
non-coding regions of the genome such as deep intronic or promoter
regions. As with any genetic test, it is important that families be
counseled about risks, benefits, limitations of genetic testing by
certified geneticists and/or genetic counselors. As molecular testing
improves at an exponential rate, it is important for families to
understand that future diagnostic opportunities may exist in the
short and long term despite given a negative test result.
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