punctata denotes a group of heterogeneous bone dysplasia characterized by punctate
calcifications of the cartilage, frequently associated with a shortening of the
limbs, cataracts, ichthyosis and alopecia, alterations of the nervous system,
mental and growth deficiencies ().
The chondrodysplasia punctata family includes a dominant autosomal form (Conradi-Hünnermann
disease), a recessive autosomal form (rhizomelic), forms linked to X recessive
(chondrodysplasiaX1) and dominant (chondrodysplasiaX2 or Conradi-Hünermann-Happle).
During the nineties two milder forms were described, tibial-metacarpal and brachytelephalangic
The rhizomelic form of chondrodysplasia punctata is a disease of the peroxisomes,
structures present in every cell in the organism, which explains the great variation
between clinical manifestations presented by the syndrome. The principle characteristics
as described in literature are severe and symmetrical rhizomelic micromelia (proximal
shortening of the limbs); punctate calcifications and alterations to the ossification
in metaphyses and epiphyses of the long bones; punctate calcifications and coronal
fissures in thoracic and lumbar vertebrae; microcephaly and delayed growth; psychomotor
retardation, spasticity and early death6. Other characteristics have been described
with variable frequency, including ichthyosis, cataracts, restricted joint mobility,
suction and deglutition difficulties, alopecia, hearing loss and visual impairment,
convulsions, hypoplasia of the optic nerve, kyphoscoliosis and spina bifida ().
Patients with rhizomelic chondrodysplasia punctata (RCP) frequently present micrognathia
on the face, malar hypoplasia, a flattened bridge and bulbous point of the nose,
with a face which appears flattened ().
In contrast with the other forms of chondrodysplasia punctata, the rhizomelic
form has a bad prognosis, with repeated respiratory infections and death during
the first two years of life ().
The rhizomelic form of chondrodysplasia is rare, with 72 cases described
in literature by 1995 ().
In 1985 it was found that RCP is a disease of peroxisomes. Despite the
number and structure of peroxisomes being normal, a functional defect of these
organelles results in an enzyme deficiency, characterized by an important decrease
in the synthesis of plasmalogen, a reduction in the oxidization of phytanic acid
and of the presence of an unprocessed peroxisomal hepatic enzyme, 3-oxoacyl-CoA
thiolase. Plasmatic phytanic acid is found to be increased and the synthesis of
plasmalogen in the fibroblasts and their content in the erythrocytes are reduced
These defects are characteristic of the syndrome, although no causal relationship
has been established between them and the clinical manifestations of the disease
It is known, however, that such biochemical alterations are resultant.
differential diagnosis includes other forms chondrodysplasia punctata, Keutel
syndrome, Zellweger syndrome, Smith-Lemli-Opitz syndrome, neonatal and classic
Refsum's disease, neonatal adrenoleukodystrophy, neonatal lupus, trisomy 21 or
18, fetal alcohol syndrome, congenital infections and the maternal use of phenytoin
or anticoagulants during gestation ().
The objective of this study is to describe a case of the rhizomelic form
of chondrodysplasia punctata, diagnosed by clinical criteria.
The patient to be described, P.P.N., was taken to the Pediatric
service of the Hospital Universitário Evangélico in Curitiba at
52 days of life, referred from their native city (Joaçaba, SC), where a
pediatric consultation was sought in response to pain and crying when the mother
manipulated the arms, dating from birth. Radiography of the skeleton was requested
at the city of origin, which showed proximal shortening of both upper and lower
limbs, with calcifications of cartilage. Ten days before internment the patient
had begun to present with coughing and episodes of cyanosis and choking after
suckling, being assessed by a cardiologist who observed rough a and intense systolic
heart murmur and. suspecting interventricular communication, indicated the use
of digoxin which the patient had not yet receiving.
The mother further
complained that the patient presented difficulties with suction at the maternal
breast, making supplementation with a bottle and cows' milk necessary. During
the first month of life there was a weight loss of 400 g, without ever having
recovered birth weight in the meantime.
The patient was born by caesarian
delivery, at full term, weighing 3,110 grams, in good condition (it was not possible
to obtain an Apgar score). The mother attended 6 prenatal consultations and there
were no intercurrent conditions during gestation, except for the fact that she
is a carrier of the hepatitis B virus. Hyperimmune immunoglobulin was administered
at birth. The mother used amoxycillin during the pregnancy and denies having used
other medication. She describes a first trimester miscarriage, of which the cause
is not known, a child of the same father, a year before the patient's birth.
The father and mother of the patient are both healthy, being 23 and 24
years old respectively and non-consanguineous. The patient has three siblings,
all healthy, but children of a different father. There is family history of congenital
cardiopathy in a paternal cousin (female), who does not present any other abnormalities.
On admission to hospital the patient presented in a regular general state
of health, pallid, without jaundice, acyanotic, eupneic and without fever. Anthropometric
evaluation: weight of 3.090 g, stature of 52 cm, cephalic perimeter of 35 cm and
thoracic perimeter of 30 cm (all below the fifth percentile). There is a flattened
bridge and bulbous point of the nose, and additionally micrognathia. Anterior
fontanelle 2x2 cm, under normal tension with juxtaposed sutures. Cardiopulmonary
auscultation revealed a rough and intense systolic heart murmur, pleuropulmonary
fields clear. Abdomen unaltered. Superior and inferior limbs presented with rhizomelic
micromelia in addition to the restricted joint mobility in fingers and knees.
Discrete spasticity is present in all four limbs and newborn reflexes are normal.
Integument is unaltered.
Figure 1 -
micromelia of the upper limbs.
Figure 2 -
micromelia of the lower limbs and restricted joint mobility in the knees.
internment, echocardiography was performed, revealing subaortic perimembranous
intraventricular communication (IVC) with moderate repercussion and interatrial
communication (IAC), ophthalmological evaluation reveled bilateral microcephaly
and a decrease in the red reflex. Abdominal ultrasound and a test of otoacoustic
emissions did not reveal alterations.
Further x-rays of the skeleton
showed bilateral cartilage calcifications, most evident at knees and shoulders.
Alterations of the cranium and spinal column were absent.
Figure 3 -
of the lower limbs showing shortening of the femurs and calcification on knees
and hips joints.
patient was discharged with a clinical diagnosis of rhizomelic chondrodysplasia
punctata, prescribed digoxin and instructions were given. Sudden death occurred
while asleep at four months.
Punctate calcifications that are symptomatic, i.e. manifesting with limited
joint mobility and pain, have been described not only with have been described
not only with chondrodysplasia, but also in children with congenital infections,
chromosomal anomalies, neonatal lupus and embryopathies caused by the use of anticoagulants
or phenytoin, among others ().
These calcifications are commonly visible with radiography during the first months
of life and, as with chondrodysplasia, tend to disappear after one or two years
of age ().
Currently, RCP diagnosis is made based on clinical characteristics which
are compatible with the syndrome, associated with biochemical findings which include
serum phytanic acid assay and investigation of plasmalogen synthesis in a fibroblast
culture. Chromosome study denotes a mutation in the PEX7 gene, 50% of which are
in the L292ter allele. More than twenty mutations have been described which result
in abnormalities of the peroxisomes. A DHAPAT deficiency (acyl-CoA: dihydroxyacetone
phosphate acyltransferase) results in RCP subtype 1. Subtypes 2 and 3 are caused
by a resuction in DHAPAT activity and alkyl-DHAP synthesis, respectively ().
The diagnosis of the subtypes of chondrodysplasia is difficult due to the
large number of manifestations which they all have in common. With the discovery
of specific genetic and biochemical markers, cases previously described have been
reclassified and new subtypes have surfaced.
There are descriptions
of cases which have been diagnosed purely by radiological and clinical criteria,
one of which does not have the biochemical alterations which are peculiar to the
The case described here presents with a face characteristic of RCP, further to
the symmetrical proximal shortening of the limbs and punctate cartilage calcifications.
At seven weeks of life the child presented feeding difficulties and anthropometric
measurements below the values expected for that age, including of the head circumference.
The diagnosis of RCP was based on the clinical criteria observed.
common characteristic of RCP is the presence of coronal fissures in vertebral
bodies. Coronal fissures of thoracic and lumbar vertebral bodies is a result of
deficient ossification, at around four months of gestation, which results in an
incomplete fusion between the anterior and posterior halves of the vertebrae ().
The punctate lesions diagnosed radiologically are resultant upon the degeneration
of cartilage, represented by chondrocytes with picnotic nuclei and eosinophilic
cytoplasm, followed by ossification ().
Rhizomelic cases exist in which, as with this patient, no coronal vertebral
fissures are presented. Despite being cited by many authors as a characteristic
which is invariably found with this syndrome, a review of previously published
cases shows that this characteristic is common, but not necessarily present ().
Cardiac lesions are not cited as common characteristics of the rhizomelic
form, being more often found among patients with Conradi-Hünermann syndrome.
Nevertheless, a review performed in 1995 found nine patients with congenital cardiac
lesions out of 72 with RCP. The most frequent types were: patent oval foramen,
persistent arteriosus ductus, atrial and ventricular septal defects, associated
or not with each other ().
The patient described here presented subaortic perimembranous IAC an IVC.
It is important to observe that patients who are diagnosed with RCP should
be accompanied at clinics, because despite the current non-existence of any specific
treatment, many of the clinical manifestations may not be present at the time
of diagnosis, but appear as the case evolves, such as alopecia, ichthyosis and
cataracts. Others tend to disappear with age such as punctate calcifications,
without leaving bone deformities. Despite this motor development is compromised,
as is cognitive development, which becomes evident in patients who survive longer.
The treatment of the principal complications which lead to death, repeated
infections of the respiratory system, is merely supportive ().