Three-Dimensional Modeling and Quantitative Assessment of Mandibular Volume in Ectodermal Dysplasia: A Case Series.

Background and Objectives: Ectodermal dysplasia (ED)-a genetic disorder-is characterized by severe tooth deficiency. We compared the mandibular volume and the sagittal and horizontal mandibular widths between patients with ED (ED group) and individuals without tooth deficiency (control group) using three-dimensional modeling. We hypothesized that the mandibular volume differs in ED cases owing to congenital tooth deficiency. Materials and Methods: We used previously obtained cone-beam computed tomography (CBCT) images of 13 patients with ED. The control group data comprised retrospective CBCT images of patients of similar age and sex with a skeletal relationship of class 1. Further, using the three-dimensional image analysis software, the tooth crowns were separated from the mandible, the mandible was reconstructed and the gonion-to-gonion distance in the mandible was marked, the distance to the menton point was measured, and the distance between the two condyles was measured and compared with the control group. Results: Overall, 46.2% and 53.8% of the participants were men and women, respectively. In the ED group, the mean age of the participants was 15.46 (range, 6-24) years, and the mean number of mandibular teeth was 4.62. Notably, the edentulous mandible volume of the ED group (27.020 mm3) was statistically significantly smaller than that of the control group (49.213 mm3) (p < 0.001). There was no difference between the two groups in terms of the marked points. For data analysis, the Shapiro-Wilk test, independent samples t-test, and Mann-Whitney U test were used. Conclusions: It has been considered that mandible volume does not develop in ED cases because of missing teeth. Modern practices, such as the CBCT technique and three-dimensional software, may be effective in identifying the true morphologic features, especially in patients with genetic syndromes affecting the maxillofacial structure.

Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia.

Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140 and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review.

Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6ß4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.

Subjective Oral Health-Related Quality of Life and Objective Oral Health in People with Ectodermal Dysplasia.

Ectodermal dysplasia (ED) refers to a heterogeneous group of genetic diseases of the skin, skin appendages, and teeth. People with ED experience a poorer oral health-related quality of life (OHRQoL) compared to the general population. The aim of this study was to examine the OHRQoL of people with ED and to measure their objective physical oral health to confirm or disprove evidence of poorer oral health in this population. To determine OHRQoL, the German version of the 14-item Oral Health Impact Profile (OHIP-14G) was used. All the participants in the study were clinically examined, and the measured parameters were recorded using the Physical Oral Health Index (PhOX). In total, 10 male and 11 female participants, with an average age of 22.0 ± 9.0 years, were included in this study. The OHIP-14G summary score was 23.9 (±15.2) points (range: 0-56 points). The PhOX summary score was 61.2 (±5.1) points (range: 22-80 points). The findings indicated that both the OHRQoL and physical oral health of the participants were highly impaired and that their objective and subjective oral health were worse than those of the general population in Germany.

Aplasia cutis congenita: a report of two cases from National Hospital Abuja, Nigeria and review of the literature.

Aplasia cutis congenita is a rare congenital abnormality first described in 1767 by cordon. It mostly appears as a solitary lesion involving various layers of the skin and sometimes the bone on the scalp, limbs or abdomen. Genetics, environmental and exogenous causes have been implicated as potential causes. Only about 500 cases have been reported globally as of 2013. Two cases of Aplasia Cutis Congenita (ACC) who presented with scalp and bone defects at birth are reported, one in a syndromic child delivered to a consanguineous family, with associated cardiac, skin and nail anomalies (likely Adams Oliver syndrome) and the other as an isolated scalp lesion. Both were large defects managed conservatively by a multidisciplinary team. The challenges of investigating and managing such complex scalp anomalies in sub-Saharan Africa are highlighted.

FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome.

BACKGROUND: Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. OBJECTIVES: To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. METHODS: Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. RESULTS: Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. CONCLUSION: This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

Cardiac manifestations and gene mutations of patients with RASopathies in Taiwan.

RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.

Thermoregulation in Ectodermal Dysplasia: A Case Series.

Ectodermal dysplasia (ED) is a rare genetic disorder occurring as a consequence of gene mutations that code for the ectoderm of the developing embryo and results in numerous disorders of varying severity. The lack of functioning sweat glands in those affected with ED leads to high infant mortality and frequent complaints of hyperthermia. Temperature control of two adolescents affected with ED was assessed by conducting heat and exercise exposures while monitoring insulated auditory canal (Tac) and skin temperatures, sweating rates, and skin blood flow. One participant was able to sweat and regulate his Tac while a second participant could not regulate Tac without a cooling intervention. The heterogeneous nature of ED, and these cases highlight the need for a case-by-case review of temperature control of individuals affected with ED. This will determine cooling strategies that would be of most benefit to the individual.

Bart syndrome associated with skeletal deformities: An uncommon case report.

Bart syndrome is a rare genetic disorder characterized by aplasia cutis congenita, epidermolysis bullosa (EB), and nail abnormalities. We reported an unusual case of Bart syndrome associated with skeletal abnormalities and bilateral clubfoot.

Topical Leptospermum Honey in the Management of Aplasia Cutis Congenita in Neonates: A Case Study.

BACKGROUND: Aplasia cutis congenita (ACC) is an uncommon, heterogeneous group of disorders characterized by focal or widespread absence of skin from certain parts of the body. Complications range from 20% to 50%; they are potentially life-threatening. There is no consensus on best treatment of ACC. We report on successful closure of aplasia cutis lesions using topical active Leptospermum honey (ALH). CASES: This article describes a case of a full-term neonate with a large ACC lesion. A conservative approach was taken in the care of this lesion, in accordance with appropriate wound care principles and the care of this medically fragile neonate. This included applying topical ALH twice a day and covering defects with a secure dressing. All lesions progressed to complete closure. Time to closure was either similar or shorter than published data. CONCLUSIONS: Our experience with these cases suggests that topical ALH may be an effective natural treatment option for neonates with ACC. This conservative management led to wound closure without topical or systemic antibiotics or prolonged hospital stay.

Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus.

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.

An Evaluation of Bone Mineral Density Using Cone Beam Computed Tomography in Patients with Ectodermal Dysplasia: A Retrospective Study at a Single Center in Turkey.

BACKGROUND The aim of this retrospective study was to compare the measurements of bone mineral density (BMD) combined with volumetric dental tomography measurements taken from three main regions selected on the lower mandible, the right mandibular, medial mandibular, and left mandibular regions, in patients with ectodermal dysplasia and age-matched and gender-matched controls. Measurement of BMD in Hounsfield units (HUs) were evaluated using three-dimensional (3D) cone beam computed tomography (CBCT) imaging. MATERIAL AND METHODS Mandibular bone tomography images were evaluated from 9 women and 5 men diagnosed with ectodermal dysplasia and a control group of 9 women and 5 men. The HU values obtained according to age and gender of the total 28 study participants were measured. Statistical analysis of the data used Student's t-test. RESULTS BMD in the ectodermal dysplasia group was significantly lower compared with the BMD in the control group. Comparison of the left and right mandibular angulus regions showed that the BMD of patients with ectodermal dysplasia was significantly lower when compared with the control group in both regions, but no significant difference was found between the two groups in the BMD of the central mandibular region. CBCT was found to be an effective method for the measurement of BMD. CONCLUSIONS In patients with ectodermal dysplasia, reduced BMD should be taken into consideration when planning surgical interventions involving bone tissue and when planning implant surgery. The results of this study may be of value in dentistry and other fields of medicine.

C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.

An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood. CASE REPORT: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45-min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case. CONCLUSION: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood.

Distinct impacts of bi-allelic WNT10A mutations on the permanent and primary dentitions in odonto-onycho-dermal dysplasia.

Odonto-onycho-dermal dysplasia (OODD) is a rare autosomal recessive syndrome characterized by multiple ectodermal abnormalities. Mutations of the wingless-type MMTV integration site family member 10A (WNT10A) gene have been associated with OODD. To date, only 11 OODD-associated WNT10A mutations have been reported. In this report, we Characterized the clinical manifestations with focusing on dental phenotypes in four unrelated OODD patients. By Sanger sequencing, we identified five novel mutations in the WNT10A gene, including two homozygous nonsense mutations c.1176C>A (p.Cys392*) and c.742C>T (p.Arg248*), one homozygous frame-shift mutation c.898-899delAT (p.Ile300Profs*126), and a compound heterozygous mutation c.826T>A (p.Cys276Ser) and c.949delG (p.Ala317Hisfs*121). Our findings confirmed that bi-allelic mutations of WNT10A were responsible for OODD and greatly expanded the mutation spectrum of OODD. For the first time, we demonstrated that bi-allelic WNT10A mutations could lead to anodontia of permanent teeth, which enhanced the phenotypic spectrum of WNT10A mutations. Interestingly, we found that bi-allelic mutations in the WNT10A gene preferentially affect the permanent dentition rather the primary dentition, suggesting that the molecular mechanisms regulated by WNT10A in the development of permanent teeth and deciduous teeth might be different.

Rehabilitation of ectodermal dysplasia patients presenting with hypodontia: outcomes of implant rehabilitation part 1.

PURPOSE: This study has evaluated the pre and post perceptions of patients with ectodermal dysplasia (ED) who have been referred to Westmead Centre for Oral Health for treatment with dental implants. METHODS: Six patients with ED and hypodontia were treated with new maxillary complete dental prostheses or fixed implant prostheses, and a mandibular fixed dental prosthesis with implants. Patient perceptions were recorded with a 10cm visual analogue scale (VAS). All patients were asked to draw a line on the VAS which best described their feelings regarding aesthetics, chewing, diet and speech. RESULTS: Improvement in aesthetics was reported for all patients with change scores ranging from +9 to +4 points. Similarly, all patients reported an improvement in chewing ability with +6 point changes in 2 patients, and +8, +3, +7 and +1 in the other 4 patients. Five out of 6 patients reported less dietary restriction with 3 patients each indicating a change of +6 points, +4 points, +3 points, and 2 patients reporting +1 point change. Speech improved by +1 point for 3 patients, whilst 1 patient improved by +6 points, a further 2 patients scored no change. CONCLUSIONS: Patients with ED treated with dental implants reported encouraging outcomes post treatment after prostheses were fitted. Follow-up from 1.6 to 6.8 years has confirmed these improvements.

Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

RASopathies are associated with a distinct personality profile.

Personality is a complex, yet partially heritable, trait. Although some Mendelian diseases like Williams-Beuren syndrome are associated with a particular personality profile, studies have failed to assign the personality features to a single gene or pathway. As a family of monogenic disorders caused by mutations in the Ras/MAPK pathway known to influence social behavior, RASopathies are likely to provide insight into the genetic basis of personality. Eighty subjects diagnosed with cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Noonan syndrome were assessed using a parent-report BFQ-C (Big Five Questionnaire for Children) evaluating agreeableness, extraversion, conscientiousness, intellect/openness, and neuroticism, along with 55 unaffected sibling controls. A short questionnaire was added to assess sense of humor. RASopathy subjects and sibling controls were compared for individual components of personality, multidimensional personality profiles, and individual questions using Student tests, analysis of variance, and principal component analysis. RASopathy subjects were given lower scores on average compared to sibling controls in agreeableness, extraversion, conscientiousness, openness, and sense of humor, and similar scores in neuroticism. When comparing the multidimensional personality profile between groups, RASopathies showed a distinct profile from unaffected siblings, but no difference in this global profile was found within RASopathies, revealing a common profile for the Ras/MAPK-related disorders. In addition, several syndrome-specific strengths or weaknesses were observed in individual domains. We describe for the first time an association between a single pathway and a specific personality profile, providing a better understanding of the genetics underlying personality, and new tools for tailoring educational and behavioral approaches for individuals with RASopathies.

Epileptic Encephalopathy in Adams-Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype.

Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior.