X-Linked Dominant Chondrodysplasia Punctata

Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and biological significance of antisynthetase antibodies Clinical picture Differential diagnosis Laboratory evaluation Prognosis and treatment References Abstract X-linked dominant chondrodysplasia punctata, (CDPX2 - MIM 302960) also known as Conradi- Hunermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton producing short stature, asymmetric shortening of the limbs and scoliosis, as well as affecting the skin, hair and eyes. Frequency is unknown. The disorder is caused by mutations in the emopamil binding protein gene, EBP, the encoded protein of which normally functions as a ∆(8)-∆(7) sterol isomerase in the cholesterol biosynthesis pathway catalysing the conversion of 8(9)-cholestenol to lathosterol. To date, over 50 separate familial and recurrent mutations have been reported with no obvious correlation between the molecular defects and the severity of the clinical phenotype. There is significant intrafamilial and interfamilial phenotypic variability in patients with EBP mutations. Affected patients require dermatological care, as regular emollient application improves skin scaliness. Scoliosis and limb asymmetry lead to premature arthritis, requiring orthopaedic input. Genetic counselling, diagnostic DNA and biochemical tests and possible prenatal diagnosis should be offered to all families.

Happle (CHH) syndrome, is characterized by skeletal abnormalities including short stature, asymmetric rhizomelic shortening of the limbs, epiphyseal stippling, and craniofacial defects (Happle, 1979).In addition, there are skin defects including striated hyperkeratosis and pigmentary defects in patterns following the lines of Blaschko.Cataracts can also be present and the hair is coarse and lusterless with areas of alopecia.The clinical phenotype of CDPX2 is variable, ranging from stillborn or lethal forms, to mild, almost clinically undetectable forms.

Etiology
Biochemical studies on CDPX2 patients demonstrated increased amounts of 8dehydrocholesterol and 8(9)-cholestenol in the plasma and tissues (Kelley et al, 1999), and subsequent molecular studies demonstrated that CDPX2 was caused by mutations in the human emopamil binding protein gene, EBP (Braverman et al, 1999;Derry et al, 1999).The EBP gene is located on Xp11.23-p11.22 (Hanner et al, 1995;Schindelhauer et al, 1996) and comprises 5 exons.The gene encodes a 230 amino acid, 4 transmembrane domain protein that functions as a ∆8-∆7 sterol isomerase with a predicted molecular weight of 27 kDa (Hanner et al, 1995;Silve et al, 1996).Further screening of EBP has identified over 50 mutations in females with CDPX2 (Has et al, 2000;Ikegawa et al, 2000;Becker et al, 2001;Herman et al, 2002;Offiah et al, 2003;Whittock et al, 2003a;Whittock et al, 2003b) and males with CDPX2 (Diaz et al, 2002;Aughton et al, 2003;Milunsky et al, 2003), as well as a female case of CDPX2 erroneously classified as CHILD syndrome (Grange et al, 2000).Of the mutations described to date, approximately 75% are nonsense, frameshift or splice site mutations that lead to a truncated protein, and 25% are missense mutations affecting essential amino acids involved in ligand binding or the insertion of the protein into the membrane.The arginine to histidine missense mutation (R147H) appears to be a frequent mutation as it has been described in patients originating from America (Braverman et al, 1999;Herman et al, 2002), Japan (Ikegawa et al, 2000;Shirahama et al, 2003), and Europe (Has et al, 2002;Whittock et al, 2003a), whereas the nonsense mutation R63X has been detected in America (Braverman et al, 1999;Derry et al, 1999;Herman et al, 2002) and Europe (Has et al, 2000;Whittock et al, 2003a).Inter and intrafamilial phenotypic variability is a major characteristic of individuals with EBP mutations and a recent study has demonstrated that intrafamilial phenotypic variation of an EBP mutation can be caused by skewed Xchromosome inactivation (Shirahama et al, 2003).At least 11 cases of males with clinical features of CDPX2 have been reported (Crovato et al, 1985;Hochman et al, 1987;Sillevis Smitt et al, 1987;De Raeve et al, 1989;Tronnier et al, 1992;Omobono et al, 1993;Happle, 1995;Sutphen et al, 1995;Diaz et al, 2002;Aughton et al, 2003;Milunsky et al, 2003).Genetically, there are several mechanisms by which a viable male could arise.Firstly, gonosomal aneuploidy that gives rise to two X chromosomes [47,XXY] would result in the rescue of a lethal mutation via the resultant X-inactivation.Secondly, postzygotic or gonadal mosaicism of the gene would result in a male with an identical phenotype as females with CDPX2.Indeed, both of these mechanisms have now been characterized and reported in surviving males with CDPX2 (Sutphen et al, 1995;Aughton et al, 2003).A third possible mechanism is the presence of a leaky or hypomorphic mutation.This less severe mutation would of course lead to a less severe phenotype than that seen in females with CDPX2.Very recently a case of a hemizygous male with atypical CDPX2 has been reported (Milunsky et al, 2003).However, due to the absence of signs of chondrodysplasia punctata it has been proposed that this male has an entirely novel clinicogenetic entity and not an atypical form of CDPX2 (Happle, 2003).The majority of male CDPX2 cases are yet to be characterised at the genetic level so the incidence of gonadal mosaicism against hypomorphic mutations remains to be deduced.

Clinical description
X-linked dominant chondrodysplasia punctata is a distinctive skin disorder which is usually associated with skeletal defects and ocular abnormalities.Affected female fetuses have been detected prenatally with hydrops and may be stillborn.Babies may be born prematurely and there may be a collodion membrane or a generalised ichthyosiform erythroderma.Within the first year linear and swirling patterns of erythroderma and scaling develop following the lines of Blaschko.The ichthyosis continues to improve with age and the adult appearance may be so subtle as to be overlooked.The hair is coarse and lusterless with patches of cicatricial alopecia.Occasionally the nails are involved with flattening and/or splitting, but the teeth are normal.Craniofacial defects include frontal bossing, epicanthic folds, down slanting palpebral fissures and a flat nasal bridge.Skeletal defects include rhizomelic shortening of the limbs, limb asymmetry, short stature, vertebral defects, scoliosis, clinodactyly and polydatyly.There may be dysplastic hips, flexion deformities of the hips, joint stiffness and talipes equinovarus (Happle, 1979).Approximately twothirds of cases have unilateral or bilateral congenital cataracts which may be accompanied by microphthalmia and/or microcornea (Happle, 1981).In addition there may be optic atrophy and sensorineural deafness.Life expectancy and Intelligence are normal in affected females.As CDPX2 is inherited in a X-linked dominant manner, it is expected to be lethal in hemizygous males (Wettke-Schafer et al, 1983).However, although rare, at least 11 cases of males with clinical features of CDPX2 have been reported (Crovato et al, 1985;Hochman et al, 1987;Sillevis Smitt et al, 1987;De Raeve et al, 1989;Tronnier et al, 1992;Omobono et al, 1993;Happle, 1995;Sutphen et al, 1995;Diaz et al, 2002;Aughton et al, 2003;Milunsky et al, 2003).Characteristic features present in these males include epiphyseal and periepiphyseal stippling, skeletal asymmetry, patchy alopecia of the scalp, brow and eyelashes, linear arrays of hypotrophic changes of the skin, structural vertebral anomalies and scoliosis.In addition, most males have developmental delay (Diaz et al, 2002;Milunsky et al, 2003).

Diagnostic methods
Diagnosis is based on radiographic, ophthalmic, dermatological, biochemical and molecular investigations.The epiphyseal stippling seen in this condition affects the enchondral bone and may be more widespread than in other forms of chondrodysplasia punctata, also affecting the larynx and vertebrae.The stippling often resolves in infancy.Clinical examination of the eyes, hair, nails and skin should help to confirm the distinctive clinical features of this condition.Dystrophic calcification in the keratotic follicular plug is a distinctive histopathologic feature of CDPX2 in newborns and is not seen in any other form of ichthyosis (Hoang et al, 2004).The clinical diagnosis should be confirmed by a sterol analysis of plasma or tissue in which elevated levels of 8-dehydrocholesterol and 8(9)cholestenol are characteristic.However, where possible direct sequencing of the EBP gene should also be performed to confirm the diagnosis as sterol profiling can occasionally be misleading (Whittock et al, 2003a).Neither sterol profiles, nor mutations can give an indication of the severity of the clinical phenotype, although it has been suggested that truncating mutations lead to typical CDPX2 whereas missense mutations lead to atypical CDPX2 (Ikegawa et al, 2000).Gonosomal aneuploidy [47,XXY] as described in one male (Sutphen et al, 1995) can be determined using chromosomal analysis or FISH.

Epidemiology
Accurate incidence and prevalence data are not available for this rare disease.

Genetic counselling
As this disease is X-linked dominant then the expected offspring risk in an affected female is 50 %.Although the disease is embryonically lethal in the majority of male pregnancies, a very small number of affected males survive.An excess of miscarriages or male stillbirths have been reported in affected families.Gonadal mosaicism is common in patients with this disease (Has et al, 2000;Aughton et al, 2003) and this factor will have consequences on the genetic counselling of female sporadic cases.Clinicians should indicate that a sporadic incidence in this syndrome does not automatically mean a de novo mutation.Therefore, in calculating a recurrence risk for further pregnancies gonadal mosaicism must be considered even when dealing with a sporadic case.Genetic counselling can also prove difficult as there can be a stepwise increase in disease expression from one generation to the next (anticipation) in some families (Traupe et al, 1992;Sutphen et al, 1995).Factors that contribute to the phenomenon of anticipation may include gonadal mosaicism, random differences in X-inactivation and the reproductive fitness of those women who are affected (Traupe et al, 2000).

Antenatal diagnosis
Antenatal diagnosis has been reported in severely affected fetuses with this condition, by detecting growth retardation, skeletal asymmetry and polyhydramnios in the late 2 nd and 3 rd trimesters (Kelley et al, 1999).However, molecular antenatal diagnosis is available through identification of the syndromecausing EBP mutation using CVS (chorionic villus sample) or amniocentesis.

Management including treatment
Affected patients require dermatological care, as regular emollient application improves skin scaliness.Scoliosis and limb asymmetry lead to premature arthritis, requiring orthopaedic input.Some patients require wigs to cover extensive alopecia.Eye defects may limit visual acuity, and some patients are registered blind or partially sighted.Genetic counselling, diagnostic DNA and biochemical tests and possible prenatal diagnosis should be offered to all families.