Keywords
Campomelic dysplasia - neonate - skeletal dysplasia - 10 pairs of ribs
Introduction
Campomelic dysplasia (CD) is a rare autosomal dominant short-limbed dwarfism with
skeletal and developmental abnormalities.[1],[2] It is a rare form of skeletal dysplasia (incidence 1 in 40,000–200,000 live births)
caused by dysregulation of SOX9 expression during chondrogenesis.[3] First described in 1971 by Maroteaux et al., CD is a haploinsufficiency disorder with characteristic features of bowing and
shortening of the long bones with pretibial skin dimpling, hypoplastic scapulae, 11
pairs of ribs, a narrow thorax, and bilateral clubfeet.[4] In addition to skeletal abnormalities, hydrocephalus, hydronephrosis, and congenital
heart disease (ventriculoseptal defect, atrioseptal defect, aortic stenosis, and/or
tetralogy of Fallot) have been reported.[5] In about 10% of cases, bending of the long bones is absent, referred to as acampomelic
CD.[6] Patients severely affected with CD usually succumb to respiratory distress in the
neonatal period due to small chest, pulmonary hypoplasia, and airway anomalies.
Case Report
A preterm female neonate weighing 2420 g was born to a 23-year-old G2P1L1 mother at
36 weeks of gestation by emergency cesarean section (indication: preterm labor, previous
cesarean birth, fetal distress). There was no history of maternal fever or rupture
of membranes. She had limited prenatal care, and an antenatal scan done at 19 weeks
of gestation was normal. Both parents had normal phenotype, and there was no history
of consanguinity. The first sibling was a 3-year-old male child whose growth and development
were appropriate for age. Liquor was clear. The baby required resuscitation. Apgar
scores were 3, 5, and 8 at 1, 5, and 10 min of age, respectively. The baby developed
respiratory distress soon after birth and was referred to our unit.
The baby was admitted at 4 h of age with severe respiratory distress. Arterial blood
gas on admission showed severe mixed acidosis with pH of 6.95, PCO2 101 mmHg, PaO2
52 mmHg, HCO3 12.9 mmol/L, and BE of –15.1 mmol/L.
On examination, the baby was dull, with a temperature of 35.6°C, heart rate 158/min,
capillary refill 4–5 s, respiratory rate 78/min, subcostal retractions, audible grunt,
and SpO2 of 81%. The baby’s anthropometric measurements were as follows: weight 2420
g (37 percentile), length 41 cm (2 percentile), and head circumference 37 cm (100
percentile). The baby had flat facies, macrocephaly, large anterior fontanel (measured
5 × 4.5 cm), depressed nasal bridge, micrognathia, low set ears, short neck, small
chest, short limbs with bowing [Figure 1], and bilateral clubfeet [Figure 2].
Figure 1: Baby with short and bent limbs, small chest, short neck, and macrocephaly
Figure 2: Clubfoot of left lower limb
Figure 3: Chest X-ray showing 10 pairs of ribs, thin and slender ribs, hypoplastic scapulae,
and short vertebrae
The baby was intubated and commenced on conventional ventilation. Infantogram showed
small thoracic cage, slender thin ribs, 10 pairs of ribs, hypoplastic scapulae, bowed
tibiae, femora and ulnae, short fibulae, short and flat vertebrae, and small iliac
wings [Figure 3] and [Figure 4]. The clinical features and radiological findings were consistent with the diagnosis
of CD.
Figure 4: Infantogram showing splayed pubic symphysis, small iliac bones, short and hypoplastic
vertebrae, bowing of tibiae, femurs, ulnae, and short fibulae. Arrows indicate bent
ulna, femora and tibia
Laboratory investigations showed hemoglobin of 15.4 g/dL, leucocytosis (white blood
cell: 23,800/mm3), platelets 2.14 lakhs/mm3, and C-reactive protein of 3.8 mg/L. Blood culture was taken, and antibiotics (cefotaxime
and amikacin) were started. Head ultrasound showed dilatation of both lateral ventricles.
Ultrasound of the abdomen showed Mullerian structures. The baby had subtle seizures
at 6 h of life. The baby had normal female karyotype with 46XX chromosomes.
The parents were counseled regarding further evaluation (mutation analysis, geneticist
consultation). In view of poor prognosis, the parents deferred further care and took
the baby from hospital against medical advice.
Discussion
Osteochondrodysplasias or skeletal dysplasias are a heterogeneous group of more than
350 distinct disorders of skeletogenesis. Campomelic dysplasia (from Greek “campto,”
to bend and “melos,” limb), also known as camptomelic syndrome, or campomelic dwarfism
is a rare life-threatening genetic disorder (incidence of 1 in 40,000–200,000 live
births) caused by mutations in or near the SOX9 gene (chromosome 17). SOX9 is important
for the development of the skeleton and reproductive system.[7],[8] Mutations in SOX9 gene cause skeletal deformities, male-to-female sex reversals,
abnormal hair growth, fibrosis, and cancer.[3]
Shortness of the calf and hamstring musculature causes bowing of the tibia and femora
and characteristic skin dimples over the curved bones, especially the lower limbs.
They usually have short legs, dislocated hips, underdeveloped shoulder blades, 11
pairs of ribs instead of 12, bone abnormalities in the neck and clubfeet, small chin,
prominent eyes, macrocephaly, and flat face. In about 10% of cases, the bending of
the long bones is absent, referred to as acampomelic CD. Our case had only 10 pairs
of ribs instead of 11 pairs as reported in cases of CD.
Differential diagnoses of CD include thanatophoric dysplasia, osteogenesis imperfecta
type II, hypophosphatasia, achondrogenesis, short rib syndromes, atelosteogenesis,
mesomelic dysplasia (Reinhart variety), kyphomelic dysplasia (KD), Stüve-Wiedemann
osteochondrodysplasia, and unclassifiable varieties of congenital bowing of the long
bones. [Table 1].
Table 1
Differential diagnosis of skeletal dysplasias
|
Disorder
|
Skeletal manifestations
|
Other possible observations
|
Prognosis
|
Inheritance
|
|
AD: Autosomal dominant; AR: Autosomal recessive; HC: Head circumference; IUGR: Intrauterine
growth restriction
|
|
Achondroplasia[5]
|
Rhizomelic shortening of the limbs; frontal bossing; depressed nasal bridge
|
Trident hand; polyhydramnios
|
Intelligence and lifespan are normal; possible obstructive apnea in the infantile
period.
|
AD: mutations in the FGFR3 gene
|
|
Atelosteogenesis[10]
|
Deficient ossification of humerus, femur, thoracic spine and phalanges, micromelic
dwarfism with incurvated legs, club feet, dislocation of the elbows, club shape of
humerus and femur
|
Cleft palate
|
|
AR: mutations in the DTDST gene, gene encoding filamin B (FLNB)
|
|
Campomelic dysplasia
|
Anterior bowing of the long bones, particularly lower limbs; bell-shaped/ narrow chest;
scoliosis
|
IUGR; hydrocephalus; mild hydramnios; low set/malformed ears; ambiguous genitalia;
micrognathia
|
Neonatal or infant death due to respiratory complications in almost all cases
|
AD: mutations in the SOX 9 gene
|
|
Diastrophic dysplasia
|
Lateral projection of thumbs; normal HC; kyphoscoliosis; joint contractures; disproportionate
shortening of limbs
|
Cleft palate
|
Mortality depends on respiratory obstruction; for neonatal survivors, prognosis generally
good
|
AR: mutations in the DTDST gene
|
|
Hypophosphatasia[10]
|
Generalized lack of ossification; poorly mineralized cranium; hypoplastic, demineralized
bone
|
Polyhydramnios
|
Neonatal or infant death due to respiratory complications in almost all cases
|
AR: mutations in the ALPL gene
|
|
Kyphomelic dysplasia (KD)[6]
|
Severe localized and symmetric bowing of the femora, narrow chest, 11 pairs of ribs,
short and flared ribs, platyspondyly, metaphyseal flaring with relative sparing of
the remainder of the skeleton.
|
Micrognathia
|
Normal cranium and psychomotor development
|
AR
|
|
Osteogenesis imperfecta[5],[10]
|
Multiple in utero fractures; rib deformities; variable shortening of the long bones;
narrow thorax/funnel chest
|
Normal or mildly increased fluid
|
Depends on the severity of the specific phenotype (type I and IV, health generally
good; type II, neonatal lethal)
|
AD: mutations in either COL1A1 or
|
|
Stüve Wiedemann osteochondrodysplasia[6]
|
Bowed long bones, joint restrictions, unusual bone fractures, abnormal trabecular
pattern
|
Dysautonomia, respiratory and feeding difficulties, middle face hypoplasia
|
Death in the neonatal period and infancy
|
AR: mutations in the leukemia inhibitory factor receptor gene (LIFR)
|
|
Thanatophoric Dysplasia[10]
|
Narrow thorax/funnel chest; macrocephaly; proportionate shortening of limbs
|
Hydrocephalus; polyhydramnios; decreased fetal activity
|
Lethal micromelic dwarfism due to respiratory complications
|
AD: mutations in the FGFR3 gene
|
Thanatophoric dysplasia is diagnosed prenatally by the presence of bowed femora, frontal
bossing, cloverleaf skull, short fingers, small chest, and polyhydramnios. Limb shortening
would be obvious from as early as 13 weeks’ gestation, and our case had antenatal
scan at 19 weeks which was normal. Features of thanatophoric dysplasia like cloverleaf
skull, frontal bossing, and short fingers were not seen in our case.
Osteogenesis imperfecta type II presents with neonatal fractures, broad crumpled femora,
and beaded ribs. Our case did not have beaded ribs or fractures and femora were normal.
Prenatal lethal form of hypophosphatasia is characterized by hypomineralization and
osteochondral spurs without clinical features of CD. Atelosteogenesis is a lethal
chondrodysplasia characterized by incomplete ossification of the vertebral bodies
with coronal clefts of the lumbar vertebrae and hypoplasia of the upper thoracic vertebral
bodies, club shape of the humerus and femur, and lack of ossification of single phalanges
and metacarpals in most patients.
KD is bent bone skeletal dysplasia that has severe localized and symmetric bowing
of the femora without other significant abnormalities. Unlike CD, KD involves principally
the femora with sparing of the remainder of the skeleton.
Stüve-Wiedemann osteochondrodysplasia is a rare bent bone dysplasia characterized
by bowed long bones, joint restrictions, dysautonomia, respiratory, and feeding difficulties
leading to death in the neonatal period and infancy.
Most cases of CD result from new mutations in or near the SOX9 gene and occur in people
with no history of the disorder in their family. Genetically male (XY) individuals
appear phenotypically female because defective SOX9 gene is unable to fulfill its
role of sex differentiation (testis development). Approximately 75% of the affected
individuals with a male karyotype (46XY) have ambiguous genitalia or normal female
genitalia, which is known as sex reversal.[9] Our case had female genitalia and karyotype showed 46 XX chromosomes.
Most cases succumb during neonatal period due to respiratory failure, and around 5%
cases survive beyond infancy. Respiratory distress results from the small size of
the chest, pulmonary hypoplasia, and laryngotracheobronchomalacia which are usually
fatal in the neonatal period. Those who survive into early infancy frequently have
feeding problems and difficulty in breathing.
CD can be diagnosed antenatally through chorionic villus sampling or amniocentesis,
if the gene defect is identified in the previously affected individual.[10] In females with CD who have a Y chromosome, the gonads do not develop into normal
ovaries and should be surgically removed because of the risk of malignancy.
Conclusion
CD is a rare form of lethal skeletal dysplasia. We report a preterm neonate who presented
with respiratory distress and characteristic clinical and radiological features of
CD. To the best of our knowledge, this is the first case report of CD with 10 pairs
of ribs.
Declaration of patient consent
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