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Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report

BMC Medical GeneticsBMC series – open, inclusive and trusted201819:41

  • Received: 25 September 2017
  • Accepted: 28 February 2018
  • Published:
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Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay-Wells syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis.

Case presentation

We describe a patient presenting clinical features reminiscent of AEC syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele.


To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.


  • AEC
  • Bartsocas–Papas syndrome
  • CHUK
  • Cocoon syndrome
  • 1q21.1 microdeletion syndrome


Ectodermal dysplasias (ED, OMIM:604292) are a group of diseases affecting the teeth, hair, nails and exocrine and sebaceous glands. In some cases, part of the skin, eyes, inner ears, fingers, toes and central nervous system can also be affected. There are approximately 150 different types of ED, the most commonly recognized syndromes being the ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC, OMIM: 129900), Rapp-Hodgkin syndrome (OMIM: 129400) and ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC, OMIM:106260) [1]. AEC syndrome, also known as Hay-Wells syndrome, is caused by heterozygous pathogenic variants in TP63 [2, 3]. A classical feature of AEC syndrome is the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities, and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis [46].

IRF6-related disorders are a group of inherited disorders associated with heterozygous pathogenic variants in IRF6, including Van der Woude syndrome (VWS, OMIM:119300) and popliteal pterygium syndrome (PPS, OMIM:119500). VWS is characterized by orofacial clefting and lip pits whereas PPS is characterized by similar lip/palate abnormalities in combination with ankyloblepharon in some cases, as well as digital and genital abnormalities [7, 8]. Bartsocas-Papas syndrome (BPS, OMIM: 263650), a severe form of PPS, is associated with homozygous pathogenic variants in RIPK4 and CHUK [911]. Recently, a de novo missense variant in CHUK was reported in one patient with ectodermal dysplasia, orofacial clefting, limb anomalies and hypogammaglobulinemia [12].

Copy number variants affecting the 1q21.1 region have been associated with genomic disorders. Phenotypic features of 1q21.1 deletion syndrome include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~ 15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, and sleep disturbances (OMIM: 612474). The majority of microdeletions are inherited, and incomplete penetrance and variable expressivity have been noted [1315]. In this report, we describe, for the first time, a patient with compound heterozygous variants in CHUK. Interestingly, one variant arose de novo. To our knowledge, this is the second patient with CHUK-deficiency and immune abnormalities associated with de novo variant in CHUK. However, based on our data, it is unclear if, in some cases, de novo heterozygous CHUK variants are sufficient to cause disease. Clinical features of the patient are consistent, although less severe, with previously reported cases. This patient is also carrier of a 2 MB deletion on chromosome 1 which might contribute to some of his features.

Case presentation

Our patient is a male born to healthy non consanguineous parents weighing 2.375 kg, measuring 48 inches at birth. Maternal and paternal age were 27 and 25 years old, respectively. During the pregnancy there were no exposures to drugs, alcohol, tobacco or medications. The fetal movements were described as normal up until approximately 32 weeks gestation, when they were noted to be decreased. He was delivered by induced vaginal delivery at 37 + 4 weeks gestation due to intrauterine growth retardation and reduced fetal movements. He was transferred to the Children’s Mercy Hospital Neonatal Intensive Care Unit (NICU) on day 1 of life due to cleft lip and palate and ankyloblepharon filiforme adnatum. Physical examination revealed sparse eyelashes and eyebrows, hypoplasia of the teeth, abnormal palmar creases, 5th finger clinodactyly, mild 2nd, 3rd toe syndactyly and hypohidrosis (Fig. 1). The patient had recurrent bacterial and viral infections. His infections included recurrent otitis media despite bilateral myringotomy and tube placement, Staphylococcus aureus impetigo, coxsackie hand foot mouth disease, recurrent upper and lower respiratory infections including respiratory syncytial virus (RSV) bronchiolitis and multiple episodes of non-RSV viral bronchiolitis. His immune work up showed mild abnormalities including low immunoglobulin (Ig) M (31 mg/dL) and low normal IgG levels (355 mg/dL). His IgA was normal (17 mg/dL). His lymphocyte subsets showed normal T cells (CD3; 1860 mm3) but mildly low CD4 (1333 mm3) and CD8 (372 mm3) subsets. The patient’s developmental history was appropriate. He had a head ultrasound, abdominal ultrasound, echocardiogram and bone survey which were unremarkable. This clinical presentation led to the suspicion of an ectodermal dysplasia syndrome such as AEC syndrome, Bartsocas-Papas syndrome or Van der Woude syndrome. Gene testing for TP63, RIPK4 and IRF6 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 encompassing 18 genes (arr [hg19] 1q21.1q21.2 (145,885,645–147,929,115)). Parental studies were requested but not performed.
Fig. 1
Fig. 1

Clinical photographs of the index patient. a-b Mild 2nd, 3rd toe syndactyly, eczema, recurrent onychomadesis, recurrent skin infections causing desquamation; c the patient at 2 years of age - sparse hair, eyelashes and eyebrows, depressed flat nasal bridge, hypoplastic alae nasi, thin vermillion border, mild epicanthus, ankyloblepharon and unilateral left cleft lip and palate s/p repair

Clinical exome sequencing was performed on the affected individual with methods as previously published [1618]. Variants were filtered to 1% minor allele frequency, then prioritized by the American College of Medical Genetics (ACMG) categorization [19], OMIM identity and phenotypic assessment. This individual was found to be compound heterozygous for a frameshift variant c.1365del (p.Arg457Aspfs*6) and a missense variant c.1388C > A (p.Thr463Lys) in CHUK (NM_001278.3) (Fig. 2a). Both variants are located in exon 13 and occurred in trans, as visualized by the Integrative Genomics Viewer (IGV) tool (Additional file 1: Figure S1) [20, 21]. Sanger sequencing confirmed that the p.Arg457Aspfs*6 variant was maternally-inherited and the p.Thr463Lys was not detected in either parental sample (Fig. 2b). Paternity was confirmed using short-tandem repeat analysis. This indicates that the p.Thr463Lys variant arose de novo, but germline mosaicism in the father can’t be excluded. These variants were absent from population databases.
Fig. 2
Fig. 2

CHUK pathogenic variants and segregation studies. a Family pedigree showing segregation studies; b Sanger sequencing indicates that the c.1365del variant was maternally-inherited. The c.1388C > A (p.Thr463Lys) was not detected in either parental sample. Paternity was confirmed, indicating that the c.1388C > A variant arose de novo

Discussion & conclusion

Pathogenic variants in CHUK have been reported in 3 families to date (Table 1; Additional file 2: Figure S2): In 2010, Lahtela et al., described a Finnish family in which a homozygous loss of function variant in CHUK (c.1264C > T; p.Gln422*) was associated with Cocoon syndrome, an autosomal recessive lethal condition characterized by severe fetal malformations. Prenatal ultrasound of 2 fetuses revealed an abnormal cyst in the cranial region, a large defect in the craniofacial area, an omphalocele and immotile and hypoplastic limbs. Abnormalities of the heart, lungs, skin, bones and skeletal muscles were also observed. Both parents were heterozygous for this variant and genealogical analysis revealed a common ancestor [22]. In 2015, Leslie et al., reported a homozygous variant in the splice acceptor site of exon 10 (c.934-2A > G) in a female patient with Bartsocas-Papas syndrome born to healthy first degree cousins. Clinical manifestations included alopecia totalis (with absent eyebrows and eyelashes), wide cranial suture and fontanelle, nose and ear dysmorphisms, bilateral microophthalmia, ankyloblepharon, bilateral cleft lip and palate, genital hypoplasia, popliteal webs and skeletal abnormalities [11]. In 2017, Khandelwal et al., reported a 10-year-old female born to non-consanguineous Caucasian parents with a de novo missense variant in CHUK (c.425A > G, p.His142Arg). Clinical features of the patient included sparse hair, absent eyebrows and eyelashes, ankyloblepharon and dysplastic nails. X-rays of the hands and feet showed complex anomalies consisting of, among others, hypoplastic thumbs and 3rd–5th toe syndactyly. Other features included posterior cleft palate, retrognathia, buccal synechia, hypoplastic external genitalia, conical and fragile primary teeth and short stature (height -3.5SD and weight -3SD). Her development was marked by growth retardation, gastrointestinal reflux with swallowing problems and lower respiratory tract infections. She also had hypogammaglobulinemia. To our knowledge, a second pathogenic variant was not detected in this patient, but additional screening methods such as deletion/duplication analysis were not performed [12].
Table 1

Comparison of clinical features of patients with variants in CHUK reported in the literature and in this report


Lahtela et al., 2010 [22]

Leslie et al., 2015 [11]

Khandelwal et al., 2017 [12]

This study

Mode of inheritance



AD (?)

AR (with de novo paternal variant)


hom c.1264C > T (p.Gln422*)

hom c.934-2A > G (p.?)

het de novo c.425A > G (p.His142Arg)

comp het c.1388C > A (p.Thr463Lys) / c.1365del (p.Arg457Aspfs*6)


14 and 13 weeks gestation


10 years

30 months


Females (2 fetuses)




Family history







Alopecia totalis, absent eyebrows and eyelashes

Sparse hair, absent eyebrows and eyelashes

Sparse short scalp hair, sparse eyebrows


Underdeveloped skull bones, abnormal cyst

Wide cranial suture and anterior fontanelle, prominent occiput





Low set with overfolded helices




Missing eyes, hypoplastic eyeballs

Bilateral microphtalmia, ankyloblepharon, cloudy corneas


Mild epicanthus, ankyloblepharon


Abnormal orifice covered with skin

Cleft lip/palate (bilateral), intraoral bands

Cleft palate (posterior), buccal synechia

Cleft lip/palate (unilateral left)


Sharp protrusion

Distorted, absent alae nasi

Hypoplastic alae nasi

Depressed flat nasal bridge, alae nasi hypoplasia








Hypoplastic nipples, short sternum





High umbilical stump, umbilical cord fused to the abdominal wall. No organomegaly


Soft without organomegaly

Upper extremities

Hypoplastic, encased under skin

Short, bilateral cubital webs


Normal appearance



Small, bilateral syndactyly


Significant 5th finger clinodactyly. Single creases bilaterally

Lower extremities

Hypoplastic, encased under skin

Very short with popliteal webs extending from the upper thigh to the feet


Normal appearance. No pterygium



Fused forefeet

Bilateral toes syndactyly of three rays with dysmorphic phalanges

Mild 2nd, 3rd toe syndactyly


Abnormal transparent skin

Skin tags (scalp, right eyelid, umbilical cord, vagina)

Dysplastic nails

Light skin coloration. Mild eczema



Hypoplasia of the labia majora, labia minora, and clitoris

Hypoplastic external genitalia


Skeletal survey

Hypoplastic bones

Three metacarpal bones, hypoplasia of proximal phalanges, aplasia of distal phalanges (bilateral), absent foot bones (except the talus; left side), absent calcaneus, absent tarsal bones, hypoplasia of the foot phalanges (right side)

Hypoplastic thumbs and first metacarpals, four metatarsal bones with large proximal extremity of the 4th ray (left side) and fusion between the 4th and the 5th rays (right side)


Legend: n.a information not available, E Embryonic

*Describe a stop codon. It is part of the nomenclature convention

The CHUK gene encodes for Ikka (Inhibitor of nuclear factor kappa-B kinase subunit alpha), a catalytic subunit of the multiprotein complex IbK kinase. Studies in mice show that the Ikka protein is ubiquitously expressed with the highest levels in the developing spine, limb buds and head. It plays an important role in limb development, apoptosis of interdigital tissue and proliferation and differentiation of epidermal keratinocytes. Embryos from the Ikka-deficient mice developed to term, but died shortly after birth. The fetuses displayed several skeletal abnormalities affecting the size and the morphology of the spine, skull, forepaws and the hindpaws. Limb bones were relatively smaller and of normal shape. Microscopic evaluation of the skin revealed hyperplasia of the suprabasal layer (stratum spinosum) and absent stratum granulosum and stratum corneum. Mice heterozygous for the CHUK gene deletion are normal, viable and fertile [23].

In this report, we describe a male patient presenting with an AEC syndrome-like phenotype and recurrent infections suggestive of immune deficiency. Targeted sequencing of TP63, RIPK4 and IRF6 was negative. Microarray analysis identified a 2 MB deletion on chromosome 1 covering the distal part of the 1q21.1 region deletion. Although this pathogenic deletion is unlikely to account for all the clinical features of the patient, it could contribute to his dysmorphic facial features, small size and failure to thrive (Fig. 1, Additional file 3: Figure S3). Additionally, exome sequencing revealed that he was compound heterozygous for two novel variants in CHUK. The c.1365del (p.Arg457Aspfs*6) frameshift variant, was inherited from his unaffected mother and the c.1388C > A (p.Thr463Lys) missense variant arose de novo. This genotype is compatible with autosomal recessive inheritance and consistent with previously reported families [11, 22]. To our knowledge, only one patient has been reported so far with a de novo missense variant in CHUK [12]. Since deletion/duplication testing was not performed, the presence of a second undetected variant cannot be ruled out. Interestingly, our patient shares several clinical features with this individual. However, skeletal defects appeared less severe in our patient and we cannot rule out progressive hypogammaglobulinemia needing Ig replacement at follow up. Therefore, based on our findings, it is unclear if, in some cases, the inheritance pattern could be dominant and that de novo heterozygous CHUK variants are sufficient to cause the disease. Even if the majority of pathogenic de novo variants are involved in dominant genetic disorders, there are growing examples of recessive disorders that can be caused by the combination of an inherited variant on one allele and a de novo variant on the other.



American College of Medical Genetics


Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome


Bartsocas-Papas syndrome


Ectodermal dysplasia


Ectrodactyly-ectodermal dysplasia-clefting syndrome




Integrative Genomics Viewer


Neonatal Intensive Care Unit


Online Mendelian Inheritance in Man


Popliteal pterygium syndrome


Respiratory syncytial virus


Van der Woude syndrome



Authors would like to thank the patient and the family involved in this study. We thank our colleagues in the Center for Pediatric Genomic Medicine, Children’s Mercy Kansas City.


This work was supported by the Marion Merrell Dow Foundation, Children’s Mercy - Kansas City, Patton Trust, W.T. Kemper Foundation, Pat & Gil Clements Foundation, Claire Giannini Foundation, and Black & Veatch.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Authors’ contributions

Conceived and designed the experiments: IT, MCD, CS. Performed the experiments: MCD, IT, CS. Contributed reagents/materials/analysis tools: NM, EF. Wrote the paper: MCD, IT. Contributed to the recruitment and clinical investigations of the patient for the study: NS, KE, NR, KC, LZ, ER. All authors reviewed and agreed to the manuscript.

Ethics approval and consent to participate

The project was approved by the research ethics committee of the Children’s Mercy Hospitals.

Consent for publication

Written informed consent for publication of this case, including age, relevant medical history, symptoms and full facial photographs, was obtained from the patient’s father.

Competing interests

Authors declare that they have no competing interest.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO, USA
Division of Clinical Genetics, Children’s Mercy Hospital, Kansas City, MO, USA
Department of Pathology and Laboratory Medicine, Children’s Mercy Hospitals, Kansas City, MO, USA
Pediatric Allergy, Asthma and Immunology Clinic, Children’s Mercy Hospitals, Kansas City, MO, USA
Dermatology Clinic, Children’s Mercy Hospitals, Kansas City, MO, USA
Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, USA
University of Missouri Kansas City, School of Medicine, Kansas City, MO, USA


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© The Author(s). 2018