Fibrodysplasia ossificans progressiva with minor unilateral hallux anomaly in a sporadic case from Northern Tanzania with the common ACVR1c.617G>A mutation
Mohammed Saleh1, Joost Commandeur1,2, Renata Bocciardi3,4, Grace Kinabo1, Ben Hamel5,&
1Department of Paediatrics and Child Health, Kilimanjaro Christian
Medical Centre, P.O. Box 2240, Moshi, Tanzania, 2Department of Internal
Medicine, Kilimanjaro Christian Medical Centre, P.O. Box 2240, Moshi, Tanzania, 3Department
of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child
Health and CEBR, Università Degli Studi di Genova, Via G. Gaslini, 5, 16147 Genova,
Italy, 4Istituto Giannina Gaslini, Medical Genetics Unit, Via G. Gaslini,
5, 16147 Genova, Italy, 5Department of Human Genetics, Radboud university
medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Ben Hamel, Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Fibrodysplasia ossificans progressiva is a rare autosomal dominantly inherited
disorder of connective tissue caused by mutations in the gene encoding for ACVR1/ALK2,
a bone morphogenetic protein type I receptor. It is mainly characterized by
congenital malformations of the great toes and the formation of qualitatively
normal bone in extra-skeletal sites leading to severe disability and eventually
death. We present a sporadic case from Northern Tanzania with a minor unilateral
hallux anomaly and the common ACVR1 c.617G>A mutation.
Fibrodysplasia ossificans progressiva (FOP, OMIM #135100) is a rare
and disabling autosomal dominantly inherited disorder of connective
tissue leading to progressive development of heterotopic ossification
(HO) in extra-skeletal
sites, i.e. the formation of qualitatively normal bone in skeletal
muscles and other connective tissues .
We present a case of FOP that was diagnosed clinically, though only a minor unilateral
hallux anomaly was present, in the paediatric department of Kilimanjaro
Christian Medical Centre (KCMC) in Moshi, Tanzania, almost 50 years
after the first FOP case was reported from Tanzania .
The case we present here is of interest because of the minimal
and unilateral hallux abnormality in the presence of the common ACVR1 c.617G>A
mutation. Also, it is the first molecularly confirmed case of FOP
in sub-Saharan Africa outside South Africa.
In October 2013, a 12-year-old girl was referred to the paediatric
clinic of KCMC with fever, weakness and headache for seven days,
which was diagnosed as malaria and treated accordingly. She had
a history of restricted movements
of arms and neck. She had pain and swelling involving the neck,
shoulders and back areas, which began when she was two years of
age. Over the following
ten years she had repeated episodes of swelling involving the neck,
shoulder and back coupled with increasing difficulty walking. At
ten years of age
she also started to experience difficulty with eating and talking
because of decreased motility of the jaw. No history of trauma
was reported. She
is the seventh child in her family of eight children and the only
affected in her extended family. On examination the patient was
febrile with distinctive
hard non-tender swellings involving the neck, shoulder and the
upper part of the back (Figure
These abnormalities were associated with limited range of movements
over the jaw, neck, shoulders and elbow joints. In addition the
patient was unable
to extend her legs because of contractures of the hamstring tendons.
Thumbs were normal. A slight hallux valgus of the right great toe
was noted (Figure
2) and confirmed radiologically (Figure
3). Additional X-rays confirmed the presence of HO lesions around
the shoulder and pelvic girdles, elbows and back. A clinical diagnosis
was made and a venous blood sample was obtained. Molecular analysis
of the ACVR1/ALK2 gene
revealed the presence of the most frequently recurrent c.617G>A (p.Arg206His)
mutation, confirming the clinical diagnosis. She was given paracetamol
for the pain and continued to be seen in our clinic.
FOP is a rare disabling inherited disorder of connective tissue with
a prevalence of 0,5 per 1 million without apparent racial, ethnic
or geographical variation . It is most frequently
caused by a recurrent heterozygous gain-of-function mutation (c.617G>A;
p.Arg206His) in the ACVR1/ALK2 gene
on chromosome 2q23, which usually occurs as a sporadic, de novo
mutation, but it may be inherited from either parent [3,4].
Other mutations may lead to a variant phenotype .
Mutations cause an enhanced BMP-mediated signalling leading to
progressive development of HO in skeletal muscles and other connective
the formation of qualitatively normal bone in extra-skeletal sites
The case reported in this study appears to be sporadic, since neither
parent nor other first-degree relatives are known to be affected.
When present, FOP can be diagnosed clinically early in life and
even prenatally ,
by the presence of short malformed halluces (monophalangism, hallux
valgus and/or malformed first metatarsal). Sometimes similar malformations
thumbs are also present. Our case had just a minor and unilateral
hallux valgus and still the common ACVR1 c.617G>A mutation. Though
this has been reported before, it is rare .
The disease progresses with sporadic exacerbations (flare-ups) resulting in HO,
which starts in the dorsal, axial, cranial and proximal regions
of the body. The heart, smooth muscles and the diaphragm are most
notably not affected
by this disease. Flare-ups can be induced by different triggers
such as trauma, surgery, diagnostic biopsies, intramuscular injections
infections. Also, general anaesthesia poses dangers to patients
with FOP .
FOP is often misdiagnosed . From Nigeria a case was reported
where FOP was misdiagnosed as Burkitt´s lymphoma . We
know of another case in our hospital which was misdiagnosed as Burkitt's lymphoma
and in whom a diagnostic liver biopsy contributed in our opinion to the development
of HO at the abdominal wall. Another article from Nigeria demonstrated the negative
effect of surgical intervention in children with undiagnosed FOP .
These articles show the iatrogenic harm that can be done by not recognising FOP
in time. HO eventually leads to impaired mobility, weight loss due to ankylosis
of the jaw and thoracic insufficiency due to costovertebral malformations. Median
age of survival is 40 years , however, we hypothesize
that this may be lower in sub-Saharan African patients due to delayed diagnosis
and higher risks of trauma and infections. Currently, there is no effective prevention
or cure for this disabling disease.
Early diagnosis of FOP, which in cases with a minor and unilateral
hallux anomaly supposes a high level of awareness, is important
in order to prevent flare-ups, for example by restricting activities
to reduce the risk
of trauma and by reducing the number of unnecessary (invasive)
investigations and interventions, thereby preventing iatrogenic
The authors declare no competing interests.
MS and GK diagnosed and managed the patient. MS helped draft the
manuscript. BH and JC conceived the article and wrote the manuscript.
RB carried out the molecular genetic studies. All authors read and approved
the final manuscript.
We are thankful for the contributions of Drs Marieke Dekker and William
Howlett of Kilimanjaro Christian Medical Centre, Moshi, Tanzania
in preparing this article. Prof Roberto Ravazzolo of Istituto Giannina
Italy is gratefully acknowledged for allowing the molecular analysis
to be performed in his laboratory free of charge.
Figure 1: FOP lesions on the back
Figure 2: hallux valgus
of the right great toe
Figure 3: radiograph, showing the hallux valgus of the right great toe
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