Introduction
Skeletal dysplasias (SDs), or osteochondrodysplasias (OCDs), are a group of bone disorders
with clinical and etiological heterogeneous characteristics. They affect the bone
tissue and cartilage, resulting in changes in the growth, shape and development of
the skeletal system. The OCDs can be very rare; however, as a group, their prevalence
is estimated at around 2.4 per 10,000 live births[1 ]
[2 ], with the lethal SD forms corresponding to 0.95-1.5 per 10,000 births.[1 ]
[2 ]
[3 ] It is known that there are more than 456 entities classified into 40 categories
by their cardinal features (radiological findings, molecular etiology, inheritance),
among which 40% can be already detected in the perinatal period, representing 9 deaths
per 1,000 births.[1 ]
[4 ]
Osteogenesis imperfecta type II (OI type II) comprises 14% of lethal SDs, and is the
second most common cause, among thanatophoric dysplasia (26%) and the achondrogenesis
(9%) group, which represents 40–60% of all lethal SDs.[1 ]
[5 ]
[6 ]
[7 ] Osteogenesis imperfecta type II is a genetic disorder of the connective tissue characterized
by severe bone fragility, susceptibility to severe deformities, and the occurrence
of several pathological fractures, with predominance of de novo autosomal dominant
inheritance caused by mutations in genes COL1A1 and COL1A2 .[8 ] Multiple fractures are frequent in utero, and perinatal death occurs in the majority
of cases,[9 ] where most prenatal diagnosis are suspected primarily by early fetal ultrasound,
and confirmed by skeletal radiography, autopsy and, less frequently, by molecular
tests.
Due to the suspicion of a presumptive diagnosis of SD based on early gestational ultrasound
findings, a range of clinical diagnosis with different outcomes may be considered.
Based on the severity of the condition, such considerations and observations can impose
difficulties to an appropriate clinical management of these fetuses, the pregnant
women, and their families regarding genetic counselling.
In face of a medical emergency for the fetus with a presumed lethal SD, and the presence
of a rather uniform gestational ultrasound phenotype among lethal SDs, clinical management
guidelines become crucial. They may assist physicians to define proper etiological
diagnosis and clinical prognosis, as well as genetic counselling, once few of these
genetic disorders may present with considerable recurrence risks.
This article aims, through the presentation of a clinical case of a lethal SD with
radiological features (OI type IIA), to review the most common lethal SDs in the perinatal
period, highlight their clinical and radiologic features, and compare the reported
case with the literature. Furthermore, recommendations for the clinical management
of similar cases are discussed.
Clinical Case Description
A 33-year-old pregnant woman in her 6th pregnancy, with 5 previous vaginal deliveries,
was referred to our outpatient prenatal clinic due to a malformation in her fetus
detected by an ultrasound in the Family Care Clinic. Her family history was unremarkable.
A prenatal ultrasound fetal biometry at 23 weeks of pregnancy revealed an estimated
fetal weight of 505 g and shortening of the long bones, so the hypothesis of an SD
was considered. At 39 weeks of pregnancy, an ultrasound revealed an estimated fetal
weight of 815 g and fetal malformations characterized by hypotelorism, short and saddled
nose, micrognathia with redundancy of soft tissue in the face and neck, very short
ribs, and narrow thoracic cage ([Fig. 1a ]). Furthermore, it was possible to observe skeletal abnormalities with shortening
of the limbs more pronounced in the femora and humeri. Fetal hypocalcification of
the skull was evident, and complete and normal visualization of the encephalon, cerebral
hemispheres, ventricles and the posterior fossa was apparently present. A fetal echocardiography
showed normal cardiac activity, with a thoracic diameter well below the third percentile,
in addition to the presence of a mild to moderate tricuspid regurgitation. The small
thoracic diameter suggested a high probability of severe pulmonary hypoplasia.
Fig. 1 Obstetric ultrasound and fetal development quantile curves of OI type IIA – 38 weeks.
A history of Zika virus infection was suspected when the mother was 20 weeks and 4
days pregnant due to clinical manifestations described as arthralgia during 10 days,
moderate fever, and erythematous exanthema spots on the body. Real-time polymerase
chain reaction (PCR) for Zika virus could not be performed.
At 39 weeks and 3 days of gestational age, the patient delivered a singleton male
live newborn with facial malformation and very short limbs. The Apgar score was 1
for the 1st minute of life, and 0 for the 5th minute. The newborn died due to cardiorespiratory
arrest 15 minutes after birth. A post-mortem examination of the baby was performed
after we obtained the parents' authorization, and it included skeletal X-ray scans.
Genetic molecular tests were not performed ([Fig. 2 ]).
Fig. 2 (a) Patient ectoscopy: very short and deformed long bones; excess and wrinkled skin
on a deformed face and neck; (b) non-ossification of the skull with transparent meninges;
(c) extremely small thoracic cage; (d) typical babygram X-ray scan of a patient with
a case of osteogenesis imperfecta type II.
The anatomopathological study revealed a deformed neonate boy measuring 38 cm (below
the 3rd percentile) and weighing 1,800 g (below the 3rd percentile), with extreme
shortening of all members. The skull was very soft, with no cranium ossification,
and visualization of the meninges was evident. A narrow thoracic cage was present,
and the shortening and deformities of the limbs were significant. The internal examination
did not reveal any specific findings, except an important pulmonary hypoplasia ([Fig. 2 ]).
The radiographic images of the skeleton showed extreme shortening and deformity of
the long bones with severe loss of ossification, especially on the skull. The bones,
in general, presented an abnormal morphology, with “crumpled” humeri and femora, abnormally
shaped ribs containing numerous fractures (“pearl appearance”), and a vertebral column
with flattened vertebrae (platyspondylia) ([Fig. 2 ]).
Based on the clinical and radiological evidences, the patient was diagnosed as having
OI type IIA (lethal form) ([Figs. 1 ], [2 ], [3 ]).
Fig. 3 Most common types of lethal skeletal dysplasias: (a) osteogenesis imperfecta type
IIA; (b) thanatophoric dysplasia type I; (c) thanatophoric dysplasia type II (observe
the “cloverleaf” skull); (d) achondrogenesis type I; (e) fibrochondrogenesis; (f)
hypophosphatasia.
Discussion
The lethal forms of SD represent a group of genetic disorders that are clinically
and genetically heterogeneous, and whose cardinal manifestations are observed in the
perinatal period with severe and prominent phenotypic features. The majority of deaths
result from respiratory insufficiency due to pulmonary hypoplasia, with 23% of stillbirths
and 32% of babies not surviving the first week of life.[1 ]
[4 ] In a clinical routine basis, the diagnosis of lethal SD occurs more frequently in
the second trimester of gestation, through ultrasound findings (85%) and changes related
to bone mineral density, including pathological fractures, growth deficiency, rib
abnormalities, bowing or shortening of the long bones, and abnormal skull ossification,
can be observed.[10 ] However, the ultrasonography findings do not always point to a specific SD, which
may lead to an imprecise diagnosis, uncertainties and high expectations from the healthcare
professionals and parents. In addition, due to the low incidence of lethal SDs, the
presence of variable phenotypes, overlapping features and the lack of a positive family
history, it is difficult to achieve a specific etiological diagnosis and, therefore,
a clinical prognosis may be uncertain to access.
In the presence of an ultrasound finding indicative of a possible lethal SD, complementary
tests can be of clinical relevance to document each case, such as three-dimensional
(3D) ultrasound, magnetic resonance imaging with 3D reconstruction, and invasive methods
for collecting material for molecular investigation through DNA extraction from the
amniotic fluid or cordocentesis.[11 ] In spite of being useful and of facilitating the visualization of the anatomical
structures, there are exams that might be harmful to the fetus on account of the exposure
to radiation, such as computed tomography, and others that present limitations in
their interpretation due to the overlapping of fetal and maternal structures, such
as the X-ray. However, the latter plays an extremely important role in the definition
of phenotypic features in the post-natal period, especially when an SD is suspected.
In addition to radiography, autopsy and collecting material for molecular investigation
through fetal DNA analysis are ideal. Even so, in the absence of confirmatory genetic
tests, a range of differential diagnoses of lethal SDs must be considered based on
the clinical and radiological findings ([Fig. 3 ]).
The most common lethal SDs are thanatophoric dysplasia, OI type II, and the achondrogenesis
group, which comprise 40 to 60% of the cases ([Fig. 3 ]). In a study conducted from 2010 to 2014, patients with a suspicion of SD were registered
through the epidemiological birth defects program called Latin American Collaborative
Study of Congenital Malformations (ECLAMC, in the Portuguese acronym).[12 ] The clinical and radiological examinations, as well as photographs, were evaluated
when available based on a methodology with modifications proposed by Barbosa-Buck
et al.[13 ] Three different diagnostic evidence levels (DELs) were established: DEL-1 (good
quality X-rays and/or positive genotype, and/or follow-up clinical information defining
the diagnosis); DEL-2 (satisfactory description of the clinical and radiological examinations
to establish one or more probable diagnoses); and DEL-3- (clinical data and images
with just enough quality to classify them as SDs).
Among 5,460 births, 1,452 newborns (26.6%) showed birth defects (2010–2014 ECLAMC
survey, National Institute Fernandes Figueira). Among them, 32 babies (2%) had a suspicion
of SD. The ultrasonographic diagnosis was suggestive in 93.7% of the pregnancies,
and lethality during the prenatal period occurred in 81.2% of cases. In 50% of them,
lethality was suspected after gestational ultrasounds. Out of 18 cases classified
as DEL-1, 10 were of thanatophoric dysplasia (31.2%), 4 were of OI type II (12.5%)
and there were 4 other cases each of diastrophic dysplasia, Verma-Naumoff syndrome,
achondrogenesis and fibrochondrogenesis ([Table 1 ]).[14 ]
[15 ] Among the DEL-2 group, 6 cases had the following preliminary diagnosis: fibrochondrogenesis
or Schneckenbecken dysplasia; opsismodysplasia; diastrophic dysplasia group (atelosteogenesis);
hypochondroplasia; hypochondrogenesis; and campomelic dysplasia (OMIM, 2016).[16 ]
Table 1
Clinical, radiological and genetic characteristics in different lethal skeletal dysplasias[14 ]
[15 ]
Diagnosis
(Online Mendelian Inheritance in Man [OMIM])
Clinical
features
Radiographic
characteristics
Gene
Mode of
inheritance
Fibrochondrogenesis I
(# 228520)
Rhizomelia, omphalocele, medial cleft palate, abnormal and flat nose
Enlarged metaphysis of the long bones,
vertebrae in “pear” shape
COL11A1
AR
(recessive)
Fibrochondrogenesis II
(# 614524)
Midface hypoplasia, small and anteverted nostrils, short long bones, normal size of
hands and feet, small thorax
Enlarged metaphysis of the long bones, short long bones, hypoplastic posterior vertebrae
body, small thorax
COL11A2
AD
(dominant)
AR
Atelosteogenesis type I
(# 108720)
Hypertelorism, flat nose, hypoplastic median face, equinovarus, and polidramnia
Abscent humerus and fibula, 11 ribs, hypoplastic isquium pubis, delayed proximal and
medial phalangeal ossification
FLNB
AD
Atelosteogenesis type II (# 256050)
Hypertelorism, flat nose, cleft palate, short neck, “sandal” gap between 1 and 2 toes,
ulnar deviation of the thumbs
Platyspondylia, cervical kyphos, short ribs, dysplastic vertebrae, bifid humerus,
glenoid hypoplasia
SLC26A2
AR
Atelosteogenesis type III
(# 108721)
Polydactyly, narrow auditory conduit, hydrocephalus, low set ears
Better vertebrae ossification, uniformed ossified fibula, metacarpals and phalanges
FLNB
AD
Boomerang dysplasia
(# 112310)
Hypertelorism, flat nose, hypoplastic nasal septum, short neck with loose skin, brachydactyly,
hypoplastic nails
Delayed cranium ossification, “boomerang” shape of the femur
FLNB
AD
Short-rib syndrome type I
(# 208500)
Preaxial polydactyly, syndactyly, hypoplastic penis and imperforate anus
Metaphyseal irregularities of the long bones with terminal “spikes,” small iliac bone,
horizontal acetabular shaft, short and horizontal ribs
Not defined
AR
Short-rib syndrome type II
Medial cleft face, cleft palate, low set ears, brachydactyly, abnormal genitalia
Narrow thorax, short and horizontal ribs, highly inserted clavicle, oval tibia, premature
ossification of humeral epiphysis
IFT80
AR
Short-rib syndrome type III
(# 613091)
Short limbs, narrow and cylindrical thorax, short stature
Bowed femur and tibia, enlarged metaphysis with “spikes,” square iliac bone
DYNC2H1
DR
(digenic recessive)
AR
Short-rib syndrome type IV
(# 613819)
Short stature, short limbs, narrow and cylindrical thorax
Short and horizontal ribs, highly inserted clavicles and small scapulae, bowed radium
and humerus
TTC21B
AR
Currently, with the increasing advance in molecular diagnosis, diagnostic hypotheses
can be precisely confirmed or excluded, thereby improving the accuracy of the genetic
counselling. Hence, the importance of detailed clinical records of SD cases, including
clinical and epidemiological data, radiographs, photographs, and storage of biological
material (paraffin block-embedded tissue for DNA extraction, for example) is essential.
Gene sequencing or exome sequencing for a panel of genes related to SD are now available.[17 ]
Once an experienced clinician in lethal SDs confirms the diagnosis, genetic counselling
can be properly offered to the families.[18 ] In an autosomal dominant inheritance disease, the risk of recurrence for an affected
parent can be as high as 50%; for parents who are not affected, the risk is negligible,
as in OI type II or in the thanatophoric dysplasia group, unless there is the possibility
of occurrence of germinal mosaicism.[19 ] When an autosomal recessive inheritance condition is established, such as hypophosphatasia
or achondrogenesis, the parents are necessarily carriers, thus a 25% chance of recurrence
may occur.
In the study by Barbosa-Buck et al,[13 ] the association of advanced paternal age with de novo SD cases was shown, especially
in the thanatophoric dysplasia group. In the presence of advanced paternal age, there
is a higher risk of occurrence of new mutations (de novo) per generation compared
with advanced maternal age, especially in men, due to the large number of cell divisions
during spermatogenesis.[14 ]
If the diagnosis of an SD is certain, it is essential to assess whether it is classified
as lethal, since we should instruct parents as to the severity of the condition. In
the present case, the diagnosis of OI type IIA was established at the postnatal period,
due to radiological features consistent with the disease, such as extreme osteoporosis,
presence of multiple fractures, “crumpled long bones,” absence of calcification of
the skull, and blue sclera. Osteogenesis imperfecta type II, the most severe phenotype,
has an incidence of ∼ 1 to 2 cases per 100,000 live births,[20 ] and its effects can already be observed in the uterus. Based on subtle radiographic
differences, Sillence et al[21 ] subdivided the OI type II disorder into three further groups. Type IIA is characterized
by short, broad crumpled femora and continuously beaded ribs; type IIB, by short,
broad crumpled femora, but normal ribs or ribs with incomplete beading; and type IIC,
by long, thin, inadequately modeled, rectangular long bones with multiple fractures,
and thin, beaded ribs.[15 ]
The newborns with lethal SDs survive during a few days after birth, and rarely survive
for more than one year; the treatment involves intensive support and ventilatory assistance.
More than 60% of affected newborns die on the first day of life, and 80% die within
a week.[8 ] In most cases, death usually occurs from respiratory failure related to severe pulmonary
hypoplasia, rib fractures or unstable thoracic cage, but it can also be caused by
pneumonia, hemorrhages in the central nervous system, and associated malformations.
The treatment should focus on the relief of the symptoms and on support. The importance
of medical assistance aiming at the quality of life of the baby through a palliative
treatment to relieve the pain by means of potent analgesics should be emphasized.
As the majority of newborns die in the perinatal period, rapid and effective assistance
is essential for the patients' comfort, with minimal handling due to the risk of fractures
when it is the case, such as in this report of OI type IIA.
With the same importance, we must emphasize the relevance of medical documentation
as much as radiological plates and photographs, especially in cases in which no etiological
diagnosis has been established with certainty. The anatomopathological study is recommended
in cases in which there is presence or suspicion of associated congenital malformations,
such as polydactyly. Findings of internal malformations suggested by gestational ultrasound
should be confirmed, and they contribute to the differential diagnosis of the lethal
cases associated with congenital malformations, such as the short-rib polydactyly
group[15 ] ([Table 1 ]).
The prognosis of a lethal SD, due to the severity of the condition, is quite limited.
The physician must be used to talking to parents about the possibility of a lethal
case, which itself requires great sensitivity and empathy. The use of simple and accessible
language facilitates the decision-making in the management and treatment of such cases.
As there may be implications in the course of pregnancy and during the postnatal care,
the parents should receive multidisciplinary support and adequate guidance regarding
the continuation of pregnancy, the risks of recurrence for new pregnancies and the
postnatal care, respecting the culture, religion and the laws of each community.
Clinical management and decision-making in cases in which a lethal disease is suspected
in the prenatal period, such as a lethal SD, demands a multidisciplinary approach
coordinated by an experienced physician. Firstly, a “clinical descriptive” approach,
instead of a “need for diagnosis” approach, is mostly recommended. Secondly, all efforts
in collecting good quality documentation, including X-ray plates and photographic
material, are essential. Thirdly, biological samples (amniotic fluid, blood, paraffin
block-embedded tissue) for DNA extraction and posterior gene sequencing (exome panel
or Sanger gene sequencing) should be stored; and, lastly, autopsy, including post-mortem
X-ray plates, once the multiple congenital malformations suspected should be pursued.
The genetic counselling for a case of lethal SD will be enormously enriched with the
precise knowledge of the recurrence risks if each of these recommendations is fulfilled.
