Paula and Bobby
Parents of Lillie
What is Campomelic Dysplasia?
This rare disease is a genetic syndrome that presents with severe symptoms, especially in the newborn period.
The majority of individuals do not survive infancy due to the severity of congenital features that cause respiratory insufficiency.
Most symptoms of the condition can be diagnosed before birth through an ultrasound.
Campomelic Dysplasia Cmd1; Cmpd1 Cmpd Cmpd1/sra1
What gene changes cause Campomelic Dysplasia?
Mutations to the SOX9 gene are responsible for the syndrome. The condition is inherited in an autosomal dominant pattern but the majority of diagnosed cases are the result of a de novo mutation.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
What are the main symptoms of Campomelic Dysplasia?
One of the most severe symptoms associated with the syndrome is laryngotracheomalacia which is the weakening of the cartilage in the upper respiratory tract. This has a serious effect on the breathing of a newborn with the syndrome and impacts on the survival rate.
One of the main features of this syndrome is the bowing of the long bones in the legs and sometimes the arms too. Short legs and dislocated hips are also common. Most individuals are born with 11 pairs of ribs not 12.
Club feet and abnormalities in the development of the bones in the neck are also features.
Unique facial features of the syndrome include a small chin, prominent eyes, a flat face and large head.
Many individuals also present with what is known as the Pierre Robin sequence of symptoms: a cleft palate, a tongue positioned further back in the mouth, and a small lower jaw.
Individuals with the syndrome are also born with ambiguous external genitalia.
How does someone get tested for Campomelic Dysplasia?
The initial testing for Campomelic Dysplasia syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Campomelic Dysplasia
This information is courtesy of the London Medical Databases, the most comprehensive resource for photos and information regarding syndromes, genes, and clinical phenotypes.
"This condition is characterised by bowing of the femur and tibia, sometimes with overlying skin dimples. The main facial features are a large head, a small jaw, a cleft palate and a flat nasal bridge. The ears may be malformed and low-set. The chest is narrow and respiratory distress is common. Congenital dislocation of the hip occurs in the majority of patients, as does bilateral talipes equinovarus. A third of patients have cardiac defects (VSD, ASD, Fallot tetralogy) and a third of patients have hydronephrosis, mostly unilateral. There have been two patients with medullary cystic disease. Ambiguous genitalia occurs in the majority of patients with an XY karyotype. Other frequent malformations include laryngomalacia or tracheomalacia, hydrocephalus and arrhinencephaly. Characteristically the scapulae are hypoplastic, the iliac wings are vertical and narrow, there is poor ossification of the pubis, and non-mineralization of the pedicles of the thoracic vertebrae. The 1st metacarpals are short and there may be 11 pairs of ribs. The condition is caused by SOX9 mutations.
MacPherson et al., (1989) described two cases with all the radiological features apart from camptomelia.
Normann et al., (1993) estimated the incidence in Norway to be 1.6 per 10,000, although in other populations a birth prevalence of 1 in 200,000 has been suggested (Mansour et al., 1995).
Expression can be very variable. Savarirayan et al., (2005) reported a mildly affected man, who had a severely affected daughter.
Mansour et al., (2002) reported long term survival in five patients with the age range of 7-20 years. Complications included recurrent apnoea, kyphoscoliosis, learning difficulties (mild to moderate), short stature and dislocation of the hip.
Offiah et al., (2002) point out that surviving cases can have features of Ischio-pubic-patella syndrome (qv) and the patient reported by Lekovic et al., (2006) had cervical instability.
The differentiation from Cumming syndrome can be difficult (Watiker et al., 2005).
There are cases (Matsushita et al., 2013) with a SOX9 mutation with a mild phenotype which includes a small patella and defective ischio-pubic ossification, that might be mistaken for ""small patella syndrom"" - see elsewhere.
Maraia et al., (1991) reported a case with a de novo 17q paracentric inversion (q12;q25). Young et al., (1992) reported a case with a de novo 2;17 translocation (t(2;17)(q35;q23-q24)). Tommerup et al., (1993) studied three cases with features of camptomelic dysplasia and translocations involving 17q24-q25. Two of these cases were male and showed sex reversal. Ninomiya et al., (1995) reported a male with similar features and a 17q21 translocation. Pfeifer et al., (1999) studied translocation cases and noted that breakpoints were scattered over a 1Mb region proximal to SOX9.
Friedrich et al., (1992) pointed out that the condition can occur without overt camptomelia. They reported an affected female infant with marked joint hypermobility and reviewed cases from the literature (Bricarelli et al., 1981, Hovmoller et al., 1977, MacPherson et al., 1989). Zerres et al., (1993) and Glass and Rosenbaum (1997) reported a similar cases. Savarirayan and Bankier (1998) reported a case of acampomelic Campomelic Dysplasia with a de novo 5q;17q translocation. Friedrich et al., (2000) later reported that their case (Friedrich et al., 1992) had been found to have a SOX9 mutation. A further missense mutation in an acampomelic case was reported by Thong et al., (2000). Moog et al., (2001) also reported an acampomelic case with a missense mutation (H165Y). Follow-up to the age of two years was provided. At that stage he was able to stand and walk with support. He could not talk due to a tracheostomy, but apart from hypotonia, there was said to be no neurological dysfunction.
Foster et al., (1994); Wagner et al., (1994); Kwok et al., (1995) demonstrated mutations in the SOX9 gene, an SRY-related gene at 17q23-qter. Wirth et al., (1996) showed that in three patients with translocations the breakpoint was more than 130 kb from SOX9. Sudbeck et al., (1996) presented data suggesting that nonsense and frame shift mutations lead to truncation of the C terminal transactivating domain leading to loss of transactivation of genes downstream from SOX9. Meyer et al., (1997) studied 12 patients and concluded that there was lack of genotype/phenotype correlation with regards to sex reversal. Jakubiczka et al., (2001) reported a case with sex reversal associated with a Ala11Val mutation of the SOX9 gene. It is interesting to note that Huang et al., (1999) reported an XX individual with a 17q23-24 deletion including the SOX9 gene, with partial masculinisation of the external genitalia.
A mother and daughter reported by Lecointre et al., (2009) also had a deletion upstream from SOX9.
Cameron et al., (1996) reported a family where three sibs were affected. They demonstrated a heterozygous mutation in the affected children and gonadal mosaicism in the father. Interestingly, one sib had 46,XY true hemaphroditism, whereas another 46,XY sib had bilateral ovaries and normal female external genitalia. Another family with two affected sibs, had this recurrence as a result of somatic mosaicism (Smyk et al., 2007).
Giordano et al., (2001) reported a surviving case with a insertion mutation in nucleotide region 1453-1456 that created a mutant SOX9 open reading frame that was 201 nucleotides longer than the normal gene. Pop et al., (2005) reported an unusual case who was homozygous for a SOX9 mutation. Neither parent carried the mutation. The authors suggested that either there was a mitotic mutation followed by uniparental isodisomy, somatic crossing over or gene conversion, and gene conversion was found to be the most likely. Mutations upstream from SOX9 can also cause this phenotype.
Matsumoto et al., (2017) described a two-year-old male patient with a de novo SOX9 mutation and developmental delay, hypotonia, skeletal dysplasia, tracheomalacia and brain abnormalities. The patient also had severe hearing loss. Dysmorphic features included macrocephaly, hypertelorism, small mandible, cleft of soft palate, low set ears, and micropenis. Limb abnormalities included bilateral 2nd finger contractures and bilateral sandal gap. Brain MRI at two years of age showed ventriculomegaly, hydrocephaly, hypoplasia of the corpus callosum, diminished white matter, and atrophy of the frontal cortex."
* This information is courtesy of the L M D
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