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CORRESPONDENCE
Year : 2022  |  Volume : 67  |  Issue : 5  |  Page : 606-607
A de novo, novel frameshift deletion in Conradi-Hünermann-Happle syndrome with ten-year follow-up from birth


1 Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
2 Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Date of Web Publication29-Dec-2022

Correspondence Address:
Sheau- Chiou Chao
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_203_21

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How to cite this article:
Peng JH, Chen H, Chao S. A de novo, novel frameshift deletion in Conradi-Hünermann-Happle syndrome with ten-year follow-up from birth. Indian J Dermatol 2022;67:606-7

How to cite this URL:
Peng JH, Chen H, Chao S. A de novo, novel frameshift deletion in Conradi-Hünermann-Happle syndrome with ten-year follow-up from birth. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 31];67:606-7. Available from: https://www.e-ijd.org/text.asp?2022/67/5/606/366109




Sir,

In March 2010, our department was called to consult on a 7- h old girl displaying ichthyosiform erythroderma on the trunk and limbs except for palms and soles [Figure 1]a. There was no evidence of hypotrichosis. A month later, general erythroderma had abated, leaving ichthyosis in the linear patterns of Blaschko lines [Figure 1]b. There was no family history of chromosomal abnormalities. The symptoms pointed towards rare forms of congenital ichthyosiform erythroderma, but we were initially unable to make an accurate diagnosis, though Conradi-Hünermann-Happle syndrome (CHH), also known as X-linked dominant chondrodysplasia punctata-2 (CDPX2, OMIM 302960), was listed as a possibility. CHH is a heritable genetic disorder delineated by Happle in the late 1970 s, characterized by cutaneous, skeletal and ocular abnormalities.[1] Symptoms result from mutations in the emopamil binding protein, EBP (Xp11), and manifestations on the skin include congenital ichthyosiform erythroderma, follicular atrophoderma and cicatricial alopecia.
Figure 1: (a) Shows patient at birth with congenital ichthyosiform erythroderma but no hypotrichosis; (b) erythroderma faded at 1 month old, leaving ichthyosis along Blaschko's lines; (c) scarring alopecia is noted at 3 years old; (d) follicular atrophoderma at 5 years old

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CHH occurs almost exclusively in females, and when inherited by males is almost always lethal except for in XXY individuals. The symptoms vary greatly in severity, ranging from lethal forms and stillbirths to milder, almost asymptomatic forms. Those affected will be born with congenital ichthyosis arranged in the characteristic pattern of Blaschko lines upon a background of severe erythroderma, along with follicular atrophoderma and cicatricial alopecia on the scalp, characterized by coarse and dull hair. The erythroderma will abate in a few months, and in milder cases, ichthyosis will fade as well. However, follicular atrophoderma will remain, along with cicatricial alopecia on the scalp.[2]

Ocular symptoms may include bilateral asymmetric cataract formation, and skeletal symptoms may include the asymmetric shortening of long bones caused by punctiform calcifications in the epiphyseal regions, facial dysplasia and congenital hip dislocation, but may also be absent in milder forms. A skeletal scanography for the patient was ordered in February 2011, and developmental dysplasia of the hip and epiphyseal hypoplasia on the left side was found. There were no definite bone lesions, and joint space and alignment were acceptable.

Cicatricial alopecia on the scalp and follicular atrophoderma emerged as symptoms in 2013 and 2015 [Figure 1]c and [Figure 1]d, supported by histology examination. By this point, CHH was the only disorder to match the symptoms expressed, and mutation analysis was performed by amplification and direct sequencing of EBP exons [Figure 2], although plasma sterol metabolite analysis, another reliable method of identification,[3] was not performed due to inadequate equipment. Patient sequence [Figure 2]a indicates a novel deletion in exon 2 compared to healthy control [Figure 2]b, located at nucleotide 334 (delA), and the subsequent frameshift results in early termination of 25 amino acids downstream. Parental EBP sequences [Figure 2]c were normal, indicating a de novo mutation.
Figure 2: The DNA sequence of EBP with the location of mutation labelled with an arrow, showing (a) patient, (b) healthy control, (c) mother, (d) patient antisense sequence

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There is a wide range of disorders causing congenital ichthyosiform erythroderma,[4] but CHH remains uniquely identifiable for its particular combination of cutaneous symptoms. A longer follow-up period may be needed for patients who do not immediately express all symptoms, and a multi-disciplinary approach should be taken to screen for and correct any skeletal or ocular anomalies as they arise.

Acknowledgements

The authors would like to thank the patient and family whose cases have been reported.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet 1979;53:65-73.  Back to cited text no. 1
    
2.
Cañueto J, Girós M, Ciria S, Pi-Castán G, Artigas M, García-Dorado J, et al. Clinical, molecular and biochemical characterization of nine Spanish families with Conradi– Hünermann–Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature. Br J Dermatol 2012;166:830–8.  Back to cited text no. 2
    
3.
Kolb-Mäurer A, Grzeschik KH, Haas D, Bröcker EB, Hamm H. Conradi-Hünermann- Happle Syndrome (X-linked Dominant Chondrodysplasia Punctata) confirmed by plasma sterol and mutation analysis. Acta Derm Venerol 2008;88:47-51.  Back to cited text no. 3
    
4.
Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol 2010;63:607–41.  Back to cited text no. 4
    


    Figures

  [Figure 1], [Figure 2]



 

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