Rhizomelic Chondrodysplasia Punctata

What is Rhizomelic Chondrodysplasia Punctata?

It is a rare genetic syndrome that affects multiple parts of the body. It affects the skeletal system, presents with unique facial features, issues with the respiratory system and intellectual disability. The syndrome presents with severe health conditions, mainly related to the respiratory system, which means many individuals with the syndrome do not survive past childhood.

Syndrome Synonyms:
Brachytelephalangic Chondrodysplasia Punctata; Bcdp CDPR GNPAT RCDP RCDP1 RCDP2 RCDP3 Rhizomelic chondrodysplasia punctata

What gene changes cause Rhizomelic Chondrodysplasia Punctata?

Changes in three genes cause the syndrome.

RCDP1 is caused by mutations in the PEX7 gene.
RCDP2 is caused by mutations in the GNPAT gene.
RCDP3 is caused by mutations in the AGPS gene.
RCDP5 is caused by mutations in the PEX5 gene.

The syndrome is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Rhizomelic Chondrodysplasia Punctata?

Skeletal abnormalities are a main symptom of the syndrome. This includes a shortening of the bones found in the arms (upper) and the thighs. Another abnormality associated with the syndrome is known as chondrodysplasia punctata- it affects the growth of the long bones and generally can be diagnosed through x-rays. This in turn leads to the development of joint contracture, which is a permanent bending or stiffening of the joints.

Possible clinical traits/features:
Feeding difficulties in infancy, Flat occiput, Delayed closure of the anterior fontanelle, Dolichocephaly, Seizure, Autosomal recessive inheritance, High forehead, Hepatomegaly, Abnormality of the nasal bridge, Abnormality of the eye, Abnormality of neuronal migration, Large fontanelles, Triangular face, Central hypotonia

How does someone get tested for Rhizomelic Chondrodysplasia Punctata?

The initial testing for Rhizomelic Chondrodysplasia 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 Rhizomelic Chondrodysplasia Punctata

This information is courtesy of the London Medical Databases, the most comprehensive resource for photos and information regarding syndromes, genes, and clinical phenotypes.

"This lethal form of chondrodysplasia punctata is characterised by symmetrical rhizomelic shortening of the limbs with enlarged joints and contractures. Facial features include a mongoloid eyeslant, a depressed nasal bridge, hypertelorism, anteverted nostrils, full cheeks and cataracts. There may be ichthyosiform skin changes. At birth radiographs reveal flared metaphyses with epiphyseal stippling. There may also be stippling adjacent to the ischial and pubic bones and in the region of the larynx and sternum. Coronal clefts of the vertebrae are marked. In later infancy the bones become demineralised, the vertebrae become flattened and the epiphyseal stippling disappears. Cormier-Daire et al., (2001) point out that a ""duplicate calcaneus"" is a common part of the condition. White et al., (2003) studied 35 patients and found that 90% survived up to one year and 50% up to six years. Survivors develop microcephaly and mental retardation. Two sibs reported by Stoll et al., (2004), had in addition, epilepsy. Fifty-two percent have a cardiac defect (Huffnagel et al., 2013).
Pathological studies reveal abnormal peroxisomes in the liver. Reduced phytanic acid oxidation, defective plasmalogen synthesis and the presence of the unprocessed form of peroxisomal thiolase can be demonstrated. Acyl-CoA:dihydroxyacetone phosphate acyltransferase (DHAP-AT) levels are reduced. Brookhyser et al., (1999) reported prenatal diagnosis by enzyme analysis of an aminocentesis specimen taken at 13 weeks gestation.
Castillo-Taucher et al., (1991) reported a case with a maternally derived inv(8)(p23q13) suggesting a possible gene localisation.
Poll-The et al., (1991) reported a 9-month-old girl with the biochemical features of the condition but without limb shortening (see chondrodysplasia punctata, non-rhizomelic type). Stiff painful joints were noted at birth and cataracts developed in the first seven months, however at nine months she could sit unsupported and development was within normal limits. Barth et al., (1996) reported a 9-year-old girl with a milder form of rhizomelic chondrodysplasia punctata with unusual skeletal findings. Biochemical investigations showed that phytanic acid oxidation was intermediate between normals and classical rhizomelic chondrodysplasia punctata in fibroblasts.
Barr et al., (1993) and Wanders et al., (1992) reported cases with isolated DHAP-AT deficiency in contrast to most cases where several peroxisomal functions are impaired. Ofman et al., (1998) demonstrated mutations in the DHAPAT gene in patients with this form of the condition (RCDP2). Mota et al., (1997) reported an infant with apparent clinical and radiographic features of the condition who could not be shown to have any peroxisomal enzyme abnormalities. The child died at 3 months of age of respiratory infection. A child with RCDP2 reported by Nimmo et al., (2010) was the result of paternal isodisomy of chromosome 1.
Braverman et al., (1997), Motley et al., (1997) and Purdue et al., (1997) reported mutations in the PEX7 gene (RCDP1). This codes for a receptor for the type-2 peroxisome targeting signal (PTS2). Subramani (1997) provides a good review. Shimozawa et al., (1999) reported further mutations in two cases.
Further mutations in the pex7 gene were reported by Motley et al., (2002).
Mutations in the AGPS gene at 2q31 are found in RCDP type 3 (RCDP3). The phenotype in all three types is indistinguishable.
Muratoğlu Şahin et al. (2017) described a male patient with rhizomelic chondrodysplasia punctata due to homozygous missense mutation in the PEX7 gene. Clinical characteristics included short stature, low weight, depressed nasal bridge, prominent large forehead, prominent ears, dermatitis, bilateral cataracts, bilateral leukocoria, hypotonia, rhisomelia and movement limitation of the knees. X-rays showed metaphyseal enlargement, cortex irregularities, loss of ossification with a fragmented appearance and punctate calcifications in elbows, knees and in the femoral epiphysis. He had a sibling with similar characteristics and a tetrallogy of Fallot. Plasma phytanic acid levels were normal.

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