Key Clinical Message
Amyoplasia may be associated with genetic variations including the rare
condition PPP2R5D-related intellectual disability.
Introduction
Arthrogryposis is a complex musculoskeletal condition defined as
multiple congenital contractures affecting two or more parts of the
body.1 The overall prevalence of arthrogryposis is
estimated to be 1:3000 live births.2 Amyoplasia is a
specific cause of arthrogryposis that represents roughly one third of
all cases.2 The classic presentation of amyoplasia
includes adducted and internally rotated shoulders, extended elbows,
flexed wrists, and frequently, clubfeet.3 Amyoplasia
has long been considered to be a sporadic condition due to fetal
akinesia in utero. Until recently, no chromosomal or single gene
variants have been linked to this diagnosis.4 We
present a unique case of a patient presenting with the musculoskeletal
features of amyoplasia who was found to have a gene variant causing
PPP2R5D-related intellectual disability (MIM 616355), a rare genetic
condition associated with neurodevelopmental delay, speech impairment,
and macrocephaly.5
Case Presentation
The child is a 3-year-old white male born via cesarean section at 35
weeks gestation for uterine fibroids and polyhydramnios. The child had
been diagnosed prenatally with clubfeet noted on fetal ultrasound. At
birth, the patient experienced respiratory distress and poor feeding
necessitating a month-long hospitalization and gastrostomy tube
placement. The infant was noted to have multiple joint contractures,
hypotonia, and macrocephaly which prompted an initial genetic workup
shortly after birth. This workup yielded a normal chromosome karyotype,
chromosome microarray analysis, and FISH for trisomies 13, 18, and 21.
Additionally, testing was negative for myotonic dystrophy and spinal
muscle atrophy 1 and 2. Workup for additional anomalies included
ultrasound of the head and abdomen, brain MRI, and echocardiogram, and
all were normal for the child’s age. Ophthalmology evaluation at birth
was only significant for mild to moderate microphthalmia. Family history
was negative for neuromuscular conditions or arthrogryposis.
The child presented to a pediatric orthopedic surgeon at 7 weeks of age.
Physical exam was consistent with a diagnosis of amyoplasia. He had
adducted and internally rotated shoulders, extended elbows, and wrist
flexion contractures with no active motion in his fingers. He also had
bilateral thumb-in-palm deformities. In the lower limbs, he had stiff
hips with limited abduction and severe bilateral clubfeet scoring 20 out
of 20 on the Dimeglio scale. His knees had full range of motion. Pelvic
ultrasound and subsequent pelvic x-ray demonstrated both hips were
reduced.
Initially, the child’s orthopedic treatment regimen consisted of
stretching the upper limbs and feet. Later, hand splinting as well as
Ponseti casting for clubfeet was implemented. He underwent 3 rounds of
Ponseti casting with weekly cast changes, but his care was interrupted
by a two weeklong hospitalization due to viral gastroenteritis.
Subsequently, he underwent two additional rounds of Ponseti casting
before undergoing bilateral open tendo Achilles tenotomies to treat his
residual equinus deformity. Concurrently, he underwent a left extensor
carpi ulnaris to extensor carpi radialis brevis tendon transfer and
volar fascia release to address his left-hand deformity. Postoperative
upper and lower limb casts were applied for four weeks. At four weeks
follow up, the patient was transitioned to upper limb splints and
ankle-foot-orthoses, with parental instructions to begin range of motion
exercises. At that time, he was able to dorsiflex both feet to neutral
and had improved wrist and thumb positioning on the left side.
Throughout this period of orthopedic treatment, the patient was also
followed by the neurology service. Neurology ordered a whole exome
sequencing (WES) analysis which revealed a de novo heterozygous
c.598G>A (p.Glu200Lys) variant in the PPP2R5D gene.
Additionally, there were variants of unknown significance in 3 genes
linked to similar clinical phenotypes. These included a hemizygous
variant in the CLCN4 gene as well as heterozygous variants inFBN2 and PYROXD1 . However, in all three of these variants
of unknown significance, one of the parents is an asymptomatic
heterozygous carrier of the same variant. Additional testing revealed a
normal baseline EEG and repeat brain MRI at age one year and five months
demonstrated a paucity of white matter volume in the frontal, parietal,
and anterior temporal lobes, as well as dilation of the ventricular
system that appeared to be due to ex-vacuo change, and a persistent
cavum septum vergae. A small foramen magnum and upper cervical canal was
also noted but no impingement of neural elements was appreciated.
Recently, he was diagnosed clinically with focal seizures with altered
awareness (despite normal EEGs).
Discussion
The PPP2R5D gene encodes the protein B56δ which is an isoform of
the regulatory subunit of protein phosphatase 2A
(PP2A).6 This particular isoform is highly expressed
in the brain and is believed to be involved in cell growth, gene
transcription, and other key cellular processes.7PPP2R5D-related intellectual disability is a rare disorder caused by
mutations to this gene that is characterized by mild to severe
neurodevelopmental delay, speech impairment, and
macrocephaly.5 Other features that may be present
include: autism spectrum disorder, seizures, ophthalmologic
abnormalities, and hypotonia.5 This patient
demonstrated several of these characteristics including speech
impairment, macrocephaly, seizures, and hypotonia but has not to date
been diagnosed with autism or any ophthalmologic abnormalities. Brain
MRI findings in PPP2R5D-related intellectual disability are nonspecific.
However, this child does possess brain findings that had been previously
reported in association with PPP2R5D-related intellectual disability
including ventricular dilation (4 patients), white matter abnormalities
(1 patient), and cavum vergae (1 patient).6,8 To date,
only 23 patients with an average age of 9.3 years (range 0.3 – 53
years) have been reported in the literature with PPP2R5D-related
intellectual disability.6,8-10 Musculoskeletal
involvement in these patients is rare but has been described. Of the 23
patients previously reported, 3 had scoliosis, 1 had hip dysplasia, 1
had 3rd/4th finger syndactyly, 1 had
camptodactyly of the 4th toe, and 1 had scoliosis and
hip dysplasia.6,8-10 This child did not present with
any of these previously reported musculoskeletal findings. Instead, he
possessed the features of amyoplasia including adducted and internally
rotated shoulders, extended elbows, flexed wrists, and clubfeet.
Additionally, while orthopedic treatment in these patients has not been
explicitly described, this patient’s upper limbs and feet have been
treated with a combination of physical therapy, casting, splinting, and
surgery – as described. To our knowledge, no patient with
PPP2R5D-related intellectual disability has been concomitantly found to
have joint contractures typical of amyoplasia.
Arthrogryposis is a descriptive term rather than one specific diagnosis.
An estimated 400 unique diagnoses are believed to lead to the features
of arthrogryposis.11 It is important to identify the
underlying cause of arthrogryposis when possible as this can aid in the
implementation of appropriate treatment.1 For example,
it is beneficial to identify those with amyoplasia as these patients
typically have average to above average intelligence which gives them
the opportunity for productive and independent lives if their orthopedic
functionality is maximized.4 While several of the
distal arthrogryposes have been associated with genetic abnormalities,
amyoplasia, until recently, was not classically linked with any genetic
mutations.4,11 One recent report linked complete
absence of skeletal muscle (i.e. segmental amyoplasia) in distal
arthrogryposis type 1 patients with mutations in the MYLPF
gene.12 In another case, a patient was described with
the classic musculoskeletal features of amyoplasia as well as Leigh
syndrome, a genetic condition causing mitochondrial dysfunction, related
in his case to heterozygous variants inSURF1 .13
The child in this case report possesses a c.598G>A
(p.Glu200Lys) variant in the PPP2R5D gene. This variant has been
previously described as a cause of PPP2R5D-related intellectual
disability.5 While this patient’s variant was de
novo and not present in either parent, it is not possible to completely
exclude the possibility of parental germline mosaicism. Therefore, the
recurrence risk of PPP2R5D-related intellectual disability to siblings
is estimated to be 1%.5 This is important in the
genetic counseling of his parents, as amyoplasia has historically been
considered to be sporadic without recurrence in subsequent
offspring.4 Additionally, while this patient does
possess variants of unknown significance in other genes related to their
clinical phenotype (including a mutation in FBN2 , the gene
associated with Distal Arthrogryposis Type 9)14 in
each case, one of the asymptomatic parents possesses the same variant
making it highly unlikely these represent pathological mutations.
Similarly, though this patient could theoretically possess two
co-existing diagnoses, we consider this unlikely given the extensive
clinical and genetic evaluations.
Conclusion
This case highlights the importance of genetic evaluation in patients
presenting with atypical arthrogryposis. Additionally, it expands the
list of conditions that can present with arthrogrypotic features.
Furthermore, this is the second case reported of a patient with the
classic musculoskeletal features of amyoplasia presenting with an
underlying genetic abnormality, calling into question the traditional
understanding that amyoplasia is a non-genetic
condition.13 Continued vigilance of individuals with
arthrogryposis may prompt identification of additional causative
conditions, and possibly, additional genetic causes of amyoplasia.