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Year : 2019  |  Volume : 20  |  Issue : 3  |  Page : 255-257

Conradi–Hunermann syndrome: A rare case of chondrodysplasia punctata

Department of Pediatrics, Neonatology Unit, Government Medical College, Nagpur, Maharashtra, India

Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Rajkumar Motiram Meshram
Department of Pediatrics, Neonatology Unit, Government Medical College, Nagpur, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_148_18

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Conradi–Hunermann syndrome is a common form of chondrodysplasia punctata, inherited as X-linked dominant disorder of cholesterol metabolism due to mutation of emopamil-binding protein gene resulting in a spectrum of skeletal, cutaneous, and ocular abnormalities. One-day-old premature, cesarean-delivered female neonate admitted with xerotic, featherlike yellow-to-white hyperkeratotic scale all over the body with craniofacial defect, coarse hair, patches of cicatricial alopecia, and absent eyebrows. Baby had rhizomelic shortening of proximal limb, clinodactyly, club foot, talipes equinovarus, and bilateral congenital cataract. Radiological skeletal survey revealed punctate stippled calcification involving left femoral head epiphysis, bilateral tarsal bones, vertebral bodies of multiple thoracolumbar vertebrae, and sternum. Serum level of 8-dehydrocholesterol was elevated. Diagnosis of rare disease can be made on clinical suspicion and radiological survey in resource-limited setting.

Keywords: Chondrodysplasia punctata, Conradi–Hunermann syndrome, emopamil-binding protein gene

How to cite this article:
Meshram RM, Dandale AA, Rohadkar LA, Chirag RN. Conradi–Hunermann syndrome: A rare case of chondrodysplasia punctata. Indian J Paediatr Dermatol 2019;20:255-7

How to cite this URL:
Meshram RM, Dandale AA, Rohadkar LA, Chirag RN. Conradi–Hunermann syndrome: A rare case of chondrodysplasia punctata. Indian J Paediatr Dermatol [serial online] 2019 [cited 2020 Jan 18];20:255-7. Available from: http://www.ijpd.in/text.asp?2019/20/3/255/261874

  Introduction Top

Chondrodysplasia punctata is a heterogenous collection of group of skeletal dysplasias characterized by punctate epiphyses. Conradi–Hunermann syndrome is the most common form of chondrodysplasia punctata, which is inherited as X-linked dominant chondrodysplasia punctata (CDPX2) disorder of cholesterol metabolism that results in spectrum of skeletal, cutaneous, and ocular abnormalities, and it is also known as Conradi– Hunermann– Happle syndrome. The disorder is a result of a mutation of the emopamil-binding protein (EBP) gene encoding EBP, the 3-beta-hydroxysteroid-delta (8)-delta (7)-isomerase.[1] Estimated annual incidence has been around 1 in 400,000 births, with 95% of patients being female.[2] In additional to skin manifestations, rhizomelic limb shortening, vertebral defects, clinodactyly, cataract, and sensorineural deafness are also reported.[3] Here, we report a case of Conradi– Hunermann syndrome in the 1st week of life on the basis of clinical findings, radiological survey, and laboratory findings, which were helpful in diagnosing a rare disease in resource-limited setting.

  Case Report Top

A 1-day-old female, premature (36 weeks' gestation) neonate with birth weight of 1.8 kg, was admitted to our neonatal intensive care unit as a dysmorphic infant with diffusely scaly rash present at birth. The baby was born to a 30-year-old Gravida 3 Para 2 mother by cesarean delivery with a history of third-degree consanguinity. The mother had received adequate antenatal care and she was not suffering from diabetes, hypo/hyperthyroidism, and renal disease. There was no history of radiation exposure or teratogenic drug intake, except iron and folic acid during pregnancy. There was no history of malformed baby in family. Apgar scores were 7 and 8 at 1 and 5 min, respectively. She had no acute life-threatening events, and laboratory studies were unremarkable on admission.

On clinical examination, there was xerotic, feather-like yellow-to-white hyperkeratotic scale diffusely involving trunk and extremities [Figure 1]a. Craniofacial defects included frontal bossing, absent eyebrow, and low-set ears. Hairs were coarse with patches of cicatricial alopecia with flattening of nails. Ophthalmic “B” scan examination revealed bilateral cataract with microcornea. There were rhizomelic shortening of proximal limbs, clinodactyly, dysplastic hips, joint stiffness, club foot, and talipes equinovarus [Figure 1]b and [Figure 1]c. Systemic examination was within normal limits. Radiological skeletal survey revealed punctate stippled calcification involving left femoral head epiphysis, bilateral tarsal bones (talus and calcaneum), and vertebral bodies of multiple thoracolumbar vertebrae, sternum, and left carpal bones [Figure 2]a, [Figure 2]b, [Figure 2]c. There was shortening of left radius and ulna with mild bowing. Ultrasound abdomen, neurosonogram, and 2D echocardiography were within normal limits. Serum level of 8-dehydrocholesterol was elevated. Diagnosis of Conradi Hunermann syndrome was made on the basis of clinical findings, radiological features and elevated serum level of 8-dehydrochloesterol level. Genetic mutation study could not be performed due to financial constraints and this facility is not available in our institute. Hospital course was uneventful and baby was discharged on 20th day of life.
Figure 1: (a) Feather-like yellow-to-white hyperkeratotic scale all over the body. (b) Feather-like yellow-to-white hyperkeratotic scale. (c) Club foot and talipes equinovarus

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Figure 2: (a) Punctate calcification of epiphysis of sternum and ribs. (b) Bowing of radius and ulna. (c) Stippled calcification of bilateral tarsal bones

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  Discussion Top

Skeletal dysplasias are a heterogenous group of inheritable disorders characterized by changes in cartilage, bone development, as well as bone remodeling but can also significantly affect muscles, tendons, and ligaments.[4] Chondrodysplasia punctata is characterized by stippled calcification within the epiphysis as seen in many conditions including autosomal dominant and recessive chondrodysplasia punctata, X-linked dominant and recessive chondrodysplasia punctata, warfarin embryopathy, Zellweger syndrome, child syndrome, Trisomy 21, and congenital hypothyroidism.[5] Although cutaneous changes are observed in X-linked recessive and autosomal recessive forms, the cutaneous changes in X-linked dominant form are characteristic and striking.

CDPX2 is caused by mutation in the human EBP gene that encodes 230 amino acids and 4 transmembrane domain proteins. Approximately 75% are nonsense, frameshift, or splice site mutation. The mutation is lethal in males, but around 11 cases of males with clinical features of CDPX2 have been reported.[6],[7]

Clinical features are usually apparent at birth, but gravity of the disease may be different between the patients. The syndrome is usually associated with skeletal defect, cutaneous changes, and ocular abnormalities. Most of the affected female fetuses have been detected prenatally with hydrops. Babies may be born prematurely associated with collodion membrane or a generalized ichthyosiform erythroderma which may improve with age. Hairs are coarse and lusterless with patches of cicatricial alopecia. Skeletal defects include rhizomelic shortening of limbs, clinodactyly, dysplastic hips, joint stiffness, and flexion deformities. Unilateral or bilateral congenital cataracts may be accompanied in two-third of cases.[3] Our case had typical cutaneous changes, skeletal defect, and congenital cataract. Life expectancy and intelligence are normal in affected females. Other malformations such as congenital heart defect, kidney malformation, and central nervous system defect are also found.

Antenatal diagnosis is possible by ultrasonography in severely affected fetuses by detecting skeletal asymmetry, growth retardation, and polyhydramnios; however, molecular antenatal diagnosis is available using chorionic villus sampling or amniocentesis.[8] Diagnosis is based on clinical and radiological features and biochemical findings. Diagnosis of Conradi-Hünermann-Happle syndrome is confirmed by plasma sterol analysis showing markedly elevated levels of 8(9)-cholestenol and 8-dehydrocholesterol and by detection of a missense mutation (c.307G>A; p.E103K) in the emopamil-binding protein gene. Dystrophic calcification in the keratotic follicular plug is distinctive histopathologic finding in newborn with CDPX2.[9] Elevated levels of 8-dehydrocholesterol are characteristic. Neither sterol profiles nor mutations can give an indication of the severity of the clinical phenotype.

The treatment is multidisciplinary. Affected patients require dermatological care, orthopedic correction of defect, and prevention of blindness. Genetic counseling and prenatal diagnosis should be offered to all families as the expected offspring risk in an affected female is 50%, but there may be stepwise increase in disease expression from one generation to the next in some families' leading to difficult in genetic counseling.[5]

  Conclusion Top

Conradi–Hunermann syndrome is a rare genetic disorder characterized by skeletal defect, cutaneous, and ophthalmic changes. Punctate epiphyseal calcification is the most characteristic radiological finding with elevation of plasma and tissue sterol level. Molecular analysis confirms the diagnosis by showing the EBP gene mutation. We describe a case of Conradi Hunermann syndrome with typical clinical and radiological features and elevation of sterol level from our institute.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's guardian has given her consent for her child's images and other clinical information to be reported in the journal. The patient's guardian understands that her child's name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


We are very much thankful to the parents of the child for permitting to publish the details of the patient.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Whittock NV, Izatt L, Mann A, Homfray T, Bennett C, Mansour S, et al. Novel mutations in X-linked dominant chondrodysplasia punctata (CDPX2). J Invest Dermatol 2003;121:939-42.  Back to cited text no. 1
Dempsey MA, Tan C, Herman GE. Chondrodysplasia punctata 2, X-linked. 2011 May 31. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. Genereviews®. Seattle (WA): University of Washington, Seattle; 1993-2018.  Back to cited text no. 2
Ozyurt K, Subasioglu A, Ozturk P, Inci R, Ozkan F, Bueno E, et al. Emopamil binding protein mutation in Conradi-Hünermann-Happle syndrome representing plaque-type psoriasis. Indian J Dermatol 2015;60:216.  Back to cited text no. 3
[PUBMED]  [Full text]  
Krakow D. Skeletal dysplasias. Clin Perinatol 2015;42:301-19, viii.  Back to cited text no. 4
Whittock NV. X-linked Dominant Chondrodysplasia Punctata, Orphanet Encyclopedia; July, 2004. Available from: https://www.orpha.net/data/uk-CDPX2.pdf. [Last accessed on 2018 Dec 13].  Back to cited text no. 5
Pacault M, Vincent M, Besnard T, Kannengiesser C, Bénéteau C, Barbarot S, et al. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle syndrome. Eur J Hum Genet 2018;26:1784-90.  Back to cited text no. 6
Aughton DJ, Kelley RI, Metzenberg A, Pureza V, Pauli RM. X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet A 2003;116A:255-60.  Back to cited text no. 7
Lagos N, Cornejo N, Fernandez Merino J, Rojas C, Javier I, Garcia C, et al. EP13.09: Conradi-Hunermann-Happle syndrome, prenatal diagnosis and family generational report. Ultrasound Obstet Gynecol 2017;50:314.  Back to cited text no. 8
Yu K, Reid AT, Chen SJ, Patel RM, Donn SM, Gudjonsson JE, et al. Dystrophic calcifications point the way-unusual and early diagnostic clue of Conradi-Hünermann-Happle syndrome. JAAD Case Rep 2018;4:333-6.  Back to cited text no. 9


  [Figure 1], [Figure 2]


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