Keywords congenital insensitivity to pain with anhidrosis - CIPA -
NTRK1 gene - rigid spine - muscular dystrophy - RSMD1
Introduction
Hereditary sensory and autonomic neuropathy type IV (HSAN IV), also known as congenital
insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive inherited
disorder characterized by insensitivity to painful stimuli, high fevers (due to anhidrosis),
and intellectual disability.[1 ]
Mutations in the neurotrophic tyrosine kinase 1 (NTRK1 ) gene have been implicated in the pathogenesis of CIPA, leading to a partial or complete
absence of small myelinated and unmyelinated nerve fibers.[2 ] Insensitivity to pain usually presents in infancy as self-mutilative behavior, and
recurrent injuries. Management is largely supportive.
Congenital muscular dystrophy (CMD) with rigid-spine type 1 (RSMD1) is an autosomal
recessive subtype of CMDs associated with mutations of the SELENON gene. Affected individuals usually present in infancy or early childhood with hypotonia
and weakness, along with scoliosis and spinal rigidity.[3 ] Respiratory complications are a major cause of mortality in affected individuals.[4 ] However, there are no reported associations between CIPA and RSMD1. We describe
two biological siblings with two different rare inherited genetic disorders, the older
one diagnosed with RSMD1 and the younger with CIPA. This is the first report to describe
these conditions in the Kingdom of Bahrain.
The Cases
Case No. 1
Our first patient is a 2-year-old Bahraini male child who born to a full-term spontaneous
vaginal delivery with no perinatal complications. The child's weight at birth was
2.5 kg. His parents are first-degree cousins. The family history is notable for two
paternal uncles with an undiagnosed disorder with progressive muscular weakness and
death at a young age ([Fig. 1 ]) and a paternal aunt with muscle weakness.
Fig. 1 Pedigree.
At the age of 9 days, he presented with a history of fever. He was hospitalized and
evaluated for infectious causes with no foci identified. He was kept on antibiotics
for 5 days and later discharged home. However, he experienced a second episode of
unexplained high-grade fever within the neonatal period that was resolved in 5 days.
Sepsis work-ups, this time, including cultures, were all unremarkable.
In the first year of life, patient had recurrent hospitalizations for diarrhea and
was diagnosed with cow's milk protein allergy. He often experienced dry skin and pruritic
rash markedly on the face and lower limbs. He was also hospitalized at 16 months of
age with right knee swelling and right foot cellulitis. During a routine outpatient
visit, he was noticed to have axial and appendicular hypotonia and was referred to
neurology clinic for further investigation.
Neurological assessment at the age of 2 years revealed global developmental delay.
He could sit without support but could not stand independently. He could speak only
few words but could not form two-word sentences. He was also noticed to have marked
irritability, and self-mutilative behavior. He had unexplained and unprovoked face
striking with his arms, as well as head, banging at the wall.
Clinical examination showed an active and alert child without dysmorphic features.
Growth parameters showed a head circumference at the 3rd percentile at birth, and
below the 3rd percentile at 12 (41 cm) and 18 months (43 cm). His height and weight
are within normal limits, with height tracking consistently along the 75th percentile.
His weight tracked along the 25th percentile from birth to 15 months, and was at the
50th percentile at 18 months of age.
He had multiple scratch marks on his body, a large bleeding mouth ulcer, and several
small ulcers on his fingers. He had no organomegaly. Neurological examination showed
full extraocular movements, reactive pupils, and intact cranial nerves. There were
no focal neurological deficits. Tone was reduced while power were normal.
Initially, Lesch–Nyhan syndrome was suspected due to self-mutilative behavior, but
he had a normal uric acid level. Hearing assessment, thyroid function test, fragile
x-test, lactic acid, and ammonia levels were unremarkable. Celiac disease screening
was negative. Tandem mass spectrometry was not suggestive of any metabolic disorders.
Nerve conduction studies were not performed due to the expected difficulty in a child
with developmental delay.
A whole-exome sequencing was performed after obtaining consent from the parents. Testing
identified homozygous pathogenic (the American College of Medical Genetics and Genomics
[ACMG] class 5) variant c.1524_1531dup; p.(Val511Glyfs*39) in the NTRK1 gene, diagnostic of autosomal recessive sensory and autonomic neuropathy type IV
(HSAN IV; OMIM no.: 191315).
At the recent follow-up, the patient was still suffering from self-mutilation, causing
disfigured fingers ([Fig. 2 ]) and a large mouth ulcer. Motor development appeared to be improving (he was able
to walk and run) currently walks and runs.
Fig. 2 Auto amputated fingers.
Case No. 2
The elder sister of our case 1 is a 4-year-old Bahraini female, born at 37 weeks of
gestation after an uncomplicated pregnancy and a spontaneous vaginal delivery.
The patient was brought to the pediatric clinic at 2.5 years of age when her parents
noticed that she had difficulty standing up from a seated position. The child had
previously been able to stand with ease, but was gradually experiencing lower limb
weakness most notable when waking up in the morning. The mother noticed that the child
would hold on to objects for support when attempting to stand up. The child was previously
healthy. Growth was normal, and the child met appropriate speech and social development
milestones. At presentation, she was able to speak in sentences, alternate feet down
stairs, walk up, and down stairs but could not ride a tricycle or hop on one foot.
Clinical examination showed an alert, active child. No apparent dysmorphic features
noted. She had normal growth parameters. She displayed a mask-like face with no clear
expressions. Chest auscultation revealed no added sounds. Her abdomen was soft with
no organomegaly. Neurological examination showed both axial hypotonia and appendicular
hypotonia. She was noted to have weakness (four-fifths power in all four extremities)
and positive Gowers' sign. No atrophy or pseudohypertrophy noted. Deep tendon reflexes
were normal.
Laboratory investigations showed normal creatinine kinase levels and low vitamin D
levels (19 nmol/L). Nerve conduction studies and muscle biopsy were not performed.
Whole-exome sequencing was performed after obtaining consent from the parents.
Whole-exome sequencing revealed homozygous likely pathogenic (ACMG class 4) variant
c.1443del p.(Leu482Serfs*?) in the SELENON gene. It was consistent with a diagnosis of autosomal recessive muscular dystrophy
rigid-spine type 1 (OMIM no.: 602771).
At the most recent follow-up, she was noted to have weakness, continued to walk independently,
and attended school where her social and speech development remain unaffected.
Discussion
Case No. 1
The NTRK1 variant c.1524_1531dup p.(Val511Glyfs*39) creates a shift in the reading frame starting
at codon 511. The new reading frame ends in a stop codon 39 position downstream. This
variant has been confirmed by Sanger's sequencing.
While the worldwide prevalence of CIPA remains unknown, reports demonstrate that 50%
of cases are associated with consanguinity.[5 ] Although expression is variable, CIPA shows 100% penetrance.[5 ] Physical examination usually demonstrates loss of pain and temperature sensation
with preserved proprioception, light touch, and preserved deep tendon reflexes.[6 ] Anhidrosis is secondary to the absence of small nerve fibers in sweat glands as
evidenced in skin biopsies.[2 ] Anhidrosis leads to recurrent unexplained fevers, febrile seizures, and excessive
dryness of the skin. The diagnosis of CIPA is usually clinical and is confirmed using
genetic testing. Specific DNA tests are of limited value due to the large size of
the NTRK1 gene, as well as other genetic mutations associated with CIPA. Management is largely
supportive, and consists of minimizing injury, possible surgical correction of orthopaedic
deformities, as well as hyperthermia management.
This case study is the first of congenital insensitivity to pain and anhidrosis in
the Bahraini population. Additionally, rigid-type spinal muscular dystrophy RSMD1
has not been previously reported in Bahrain. This is also the first report worldwide
of these two seemingly unrelated genetic conditions being inherited in the same family.
Although this could be an incidental finding, it is worth considering the possibility
of an association between RSMD1 and CIPA.
While CIPA is most commonly associated with the clinical presentation of anhidrosis,
insensitivity to pain and heat intolerance, other symptoms have been frequently associated
with the disease. Features, such as developmental delay, intellectual disability,
and self-mutilative behavior,[7 ] are known features of CIPA and were prominent features of this patient's clinical
presentation. In addition, microcephaly in our patient is likely related to CIPA.
There is a previously reported case in Pakistan with CIPA and microcephaly.[8 ] Further, genetic testing did not reveal other variants that would explain microcephaly.
Our patient exhibited some features suggesting immune deficiency. There are patients
reported in the literature with CIPA and immune compromise characterized by recurrent
infections and decreased proliferative response of mononuclear cells in the peripheral
blood after exposure to stimuli (PHA, Con-A, and CD 3 X–L).[9 ]
Case No. 2
CMDs are a heterogenous group of inherited disorders characterized by hypotonia, muscle
weakness, and subsequent respiratory failure.[5 ] Several congenital muscular dystrophies have been described, each with characteristic
phenotypes and associated genotypes. CMD dystrophy with RSMD1 is an autosomal recessive
subtype of CMDs, associated with mutations of the SELENON gene. While the presence of spinal rigidity is not unique to RSMD1, it presents earlier
than in other muscular dystrophies. RMSD1 can also be inherited in an autosomal dominant
pattern.
The SELENON variant (NM_020451.3):c.1443delp. (Leu482Serfs*?) creates a shift in the reading
frame starting at codon 482 with unknown location of the terminating stop codon. This
variant has been confirmed by Sanger's sequencing.
The SELENON gene (also called SEPN1) is crucial for the production of selenoprotein N that is
involved in many functions within the body. More than a dozen SELENON gene mutations have been found to cause rigid spine muscular dystrophy 1 (RSMD1)
Respiratory complications are a major cause of mortality in affected individuals.[10 ] Noury et al reported a case with rigid-spine syndrome, as well as hereditary sensory,
and motor neuropathy (Charot–Marie–Tooth syndrome).[11 ] The clinical presentation of weakness and a positive Gower's sign in a child with
a positive family history was strongly suggestive of a congenital myopathy. However,
signs suggesting RSMD1 in particular, such as hypotonia at birth, scoliosis, and early
spinal involvement, were not exhibited in this patient.
Both case studies were limited by several factors. First, a detailed family history,
especially pertaining to the children's paternal uncles could not be obtained. Second,
the child's severe irritability and autistic features limited both the physical examination,
as well as the diagnostic work up. Ideally, a nerve conduction study should have been
conducted, although a normal result is expected in patients with CIPA. Muscle biopsy
was also deferred. Genetic testing for both parents to confirm their carrier status
is also planned to be performed.
Conclusion
Early diagnosis of CIPA may be aided by having a high index of suspicion in children
presenting with more than one episode of pyrexia of unknown origin as neonates and
infants. In addition, recurrent infections due to a possible underlying immunodeficiency
could be the primary manifestation in patients with CIPA; thus, we recommend considering
CIPA as a possible etiology of immunodeficiency in a patient with a personal or family
history of neurological disease.
