Table of Contents

HK J Paediatr (New Series)
Vol 28. No. 1, 2023

HK J Paediatr (New Series) 2023;28:36-40

Case Report

The Novel Homozygous ADCY6 c.413G>A; p.R138H gene Variant Associated with Lethal Congenital Contracture Syndrome 8 in a Female Patient with Epilepsy and Pachygyria

S Yimenicioğlu, A Kocaağa, B Paksoy


Lethal congenital contracture syndrome 8 consists of multiple joint contractures at birth, hypertonia, decreased tendon reflexes, and respiratory insufficiency. The related gene is the ADCY6 gene. The gene encodes a protein, that converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). Previous reports have suggested that Schwann cells require signaling from cAMP to initiate myelination. Here, we present a new patient with a novel homozygous ADCY6 missense variant (c.413G>A; p.R138H) with epilepsy, pachygyria, and long survival.

Keyword : ADCY6 gene; Epilepsy; Lethal congenital contracture syndrome; Pachygyria

Pediatric Neurologist, Health Ministery Eskisehir City Hospital, Eskişehir, Turkey
S Yimenicioğlu MD

Department of Genetics, Health Ministery Eskisehir City Hospital Eskişehir, Turkey
A Kocaağa MD
B Paksoy MD

Correspondence to: Dr S Yimenicioğlu

Received March 3, 2021


Lethal congenital contracture syndrome 8 consists of multiple joint contractures at birth, hypertonia, decreased tendon reflexes, and respiratory insufficiency. The related gene is the ADCY6 gene. The gene encodes a protein, that converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). Previous reports have suggested that Schwann cells require signaling from cAMP to initiate myelination. Here, we present a new patient with a novel homozygous ADCY6 missense variant (c.413G>A; p.R138H) with epilepsy, pachygyria, and long survival.

Key words ADCY6 gene; Epilepsy; Lethal congenital contracture syndrome; Pachygyria


Lethal congenital contracture syndrome (LCCS) is a severe arthrogryposis multiplex syndrome. Degeneration of anterior horn cells causes akinesia and hypokinesia. Several gene mutations associated with LCCS have been reported. It has a worldwide incidence, but it is more common in isolated populations, such as Finland and the Bedouin community in Israel.1 Patients with LCCS-8 (OMIM #616287) have hypotonia, respiratory distress, facial diplegia, areflexia, and swallowing difficulties. It is an autosomal recessive disorder with a genetic homozygous mutation in the adenylate cyclase 6 (ADCY6) gene. This gene encodes proteins that are necessary for cyclic adenosine monophosphate (cAMP) production. Previous reports have suggested that Schwann cells require signaling from cAMP to initiate the myelination.2 Four LCCS-8 patients from three families have been reported.2-4 Here, we describe a patient with a novel homozygous variant (c.413G > A; p.R138H) in the ADCY6 gene with epilepsy, pachygyria, and long survival.

Case Report

The 16-year-old female patient was admitted to the pediatric neurology outpatient clinic with the complaint of intermittent seizures for the past three years. During seizures, she had no response in her eyes; she had vision loss; she had stared; stretched backward and she had screamed. The frequency of seizures changed within a month. She started to have seizures twice a week or more frequently. Her parents were consanguineous. She was born at 3550 grams via spontaneous vaginal delivery. The baby's prenatal movements were slow. The mother had epilepsy in her childhood. The family noticed horizontal nystagmus when she was three-month-old, they noticed the limitation of movement in her arms in infancy. When she was 14 months old, her creatinine kinase level was 500 U/l (16-190). An independent seat was obtained when she was three years old. Scoliosis had progressed for four years.

On physical examination, she had a long face, limited inward eye movement, nystagmus, and dysarthria. She had a simian line on her left hand. Contractures were on all extremities (Figure 1). She could not sit without support. Deep tendon reflexes were not obtained, and Babinski's sign was bilaterally positive. Scoliosis was evident on the inspection. She had meaningful answers to the questions asked. Levetiracetam was added to valproate treatment because her epileptic episodes were genaralised and tonic-clonic. Muscle biopsy revealed extensive atrophy and focal regeneration areas. Visual evoked potential was normal. Electromyography revealed myopathy. The magnetic resonance imaging (MRI) revealed T1 hypointense and T2 hyperintense changes, white matter volume loss, and pachygyria when she was 14 months old. A brain MRI had obtained again when she was 16 years old. MRI revealed colpocephaly in both lateral ventricles, asymmetric multifocal change in the white matter, and occipital pachygyria (Figure 1). Widespread generalised synchronous spike slow-wave discharges were present in the electroencephalogram (EEG) (Figure 2). An electrocardiogram revealed a 90 beats per minute, PR interval of 0.13 seconds, corrected QT of 0.40 seconds, incomplete right branch block, inverse T wave on V1-4 derivations. The patient was later admitted to the hospital with complaints of cough and difficulty in breathing. After long-term inpatient treatment, she had respiratory distress and respiratory acidosis during sleep at night, and a bi-level positive airway pressure device was prescribed at discharge to prevent sleep apnoea attacks. Clobazam was added to the treatment because the seizures continued. Arthrogryposis multiplex congenital was considered with the current findings.

Figure 1 (a) Flair sequence in brain MRI. (b) T2 sequence brain MRI. Colpocephaly in both lateral ventricles and asymmetric multifocal change in the white matter and occipital pachygyria. (c) Posterior-anterior chest X-ray and prominent scoliosis, and clinical features of the patient. (d) The patient's family pedigree.

Figure 2 The findings of EEG. Spike-multispike wave discharges.

The patient was referred to the medical genetic outpatient clinic. Karyotype analysis of G-banding indicated a normal 46,XX karyotype. The SMN1 gene (including deletion and duplication testing) identified no causative variants. An agilent Oligonucleotide microarray to investigate copy number variants was done using the 8X60K probe. When the agilent cytogenomic (GRCH 37/hg 19) analysis program was used, there was no deletion or duplication in the patient. Whole-genome sequencing of a DNA sample was performed by MGI (DNBSEQ-G400). The data analysis using the Genemaster analysis programmer revealed a novel homozygous mutation variant in the ADCY6 gene, NM_015270.5; c.413 G>A (p.Arg138His). This variant causes a change of arginine to histidine, resulting in a failure in cAMP production. The missense change Segregation analysis revealed ADCY6 heterozygous variants for her mother, father, and sister. They did not have any clinical symptoms.

The ADCY6 c.413 G>A (p.Arg138His) missense homozygous mutation is pathogenic according to the in silico algorithm of DANN, EIGEN, FATHMM-MKL, Mutation Taster, REVEL, and SIFT. When the population frequencies of this variant are investigated, it is defined as a rare variant because the highest rate is in GnomAD and all the homozygous and heterozygous changes are 2.82%. However, the homozygous allele frequency is less than 0.005. The allele frequency (gnomAD) is 0.0198. The total population allele frequency is 0.0195, and the population allele frequency is 0.0187. The American college of Medical Genetics categorisation of this variant is "likely pathogenic" based on criteria PS1, PM3, PP3, and BS1. This variant causes clinical features consisting of the disease described by OMIM 616287. This variant is benign according to DEOGEN2, Mutation Assessor, and PrimateAI. The ADCY6 c.413 G>A (p.Arg138His) missense homozygous mutation in the NM_015270.5 transcript has not yet been reported in the ClinVar database and the mutation-related verdict has not been generated. In the mutation tester prediction tool, it is estimated that this variant has a disease-causing effect by changing the amino acid sequence and affecting the protein feature. Bioinformatics analysis of a previously unpublished inherited current mutation confirmed the pathogenicity. Phenotype-genotype analysis indicates that the variant has a significant effect on the development of the disease.


Lethal congenital contracture syndrome is a group of disorders characterised by congenital joint contractures with arthrogryposis.1,2 In 2014, Laquerriere et al3 reported 2 sibs from a consanguineous family with LCCS-8 and a homozygous missense mutation in the ADCY6 (p.R1116C) gene with distal arthrogryposis multiplex congenital. The patients had distal joint contractures, severe hypotonia, a lack of swallowing, and autonomous respiratory function. According to these clinical features, the phenotype was classified within the group of LCCS.3 Gonzaga-Jauregui et al4 reported a male patient with hypotonia, foot deformities, weakness of the distal extremities, sensory loss, and feeding difficulties. The patient had a homozygous missense mutation (p.Y992C) in the ADCY6 gene. Agolini et al2 reported a female patient with compound heterozygous mutations (c.1535+1G>A and p.Glu1003Lys) in the ADCY6 gene who presented with hypotonia at birth, decreased movement, lingual tremors, areflexia, and feeding difficulties. We reported a patient with LCCS-8. Trio whole-exome sequencing revealed a novel homozygous missense mutation (c.413 G>A) of the ADCY6 gene in the patient. Both of the parents and her sister had a heterozygous mutation (c.413 G>A) without any clinical features.

The ADCY6 gene encodes a member of the adenylyl cyclase family of proteins, which catalyzes the formation of the secondary messenger cAMP.2

Bacallao et al5 stated that the activation of cAMP was important to synchronise the differentiating responses of axon-associated Schwann cells in such a way as to accelerate and improve myelin formation in vitro. By promoting the transition from an immature to a differentiated state, cAMP was shown as an initiator with other axonal signals such as neuregulin to initiate myelin membrane packing. cAMP is seen as a control switch to function for myelination, as the simple removal of the cAMP stimulus is substantial enough to suppress the expression of myelin-associated genes.5 The LCCS-8 is also associated with severe joint contractures, reduced or absent limb movements and lethality usually after birth due to respiratory failure.2

Four cases from three families were previously reported whose deaths occurred within two-three years.2-4 The clinical characteristics of our patient are similar to those of other reported patients, but compared to them our patient is still alive. We suggest this variant (c.413G>A) can cause a less severe phenotype and longer survival compared to the previously published cases who died. Dysmorphic corpus callosum and hydrocephalus had not been reported before with LCCS-8.2 Our patient had bilateral occipital pachygyria and it was not reported before. 'Pachygyria' means 'thick gyri' with few, broadened gyri and shallow sulci caused by impaired neuronal migration. She had nystagmus. Ocular findings such as coloboma, retinal dysplasia, retinal detachments, and optic nerve hypoplasia may be seen with pachygyria. Epileptic seizures are severe and less frequent than normal, but the reason is unknown.6 In addition, the pachygyria might be the cause of refractory epilepsy in our patient. Neuronal migration may be modulated by intracellular Ca2+ and cAMP levels. Thus, experimentally stimulation of the adenyl cyclase in cerebellar granule cells may cause leading process branching. This may suggest that intracellular Ca2+ and cAMP levels are likely regulators of branching during neuronal migration. The signaling mechanisms are presently unknown.7 Arthrogryposis multiplex congenital with CNS involvement may be seen because of reduced fetal mobility causing abnormal development of the central nervous system.8 cAMP probably acts on both the peripheral and central nervous system causing symptoms of both systems. We could not assess intellectual deterioration, because there was no psychometric test done before seizures.

This case was interesting and worthy of representing the coexistence of cortical malformations with the ADCY6 gene mutations, resulting in arthrogryposis multiplex congenital with a longer survival expected than normal.

Declaration of Patient Consent

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

Conflict of Interest

The authors declare no conflicts of interest.


We are grateful to the participating family.


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2. Agolini E, Cherchi C, Bellacchio E, et al. Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6. Clin Genet 2020;97:649-54.

3. Laquerriere A, Maluenda J, Camus A, et al. Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum Mol Genet 2014;23:2279-89.

4. Gonzaga-Jauregui C, Harel T, Gambin T, et al. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep 2015;12:1169-83.

5. Bacallao K, Monje PV. Requirement of cAMP signaling for Schwann cell differentiation restricts the onset of myelination. PLoS One 2015;10:e0116948.

6. Tombul T, Milanlioglu A, Odabas F. A cause of intractable epilepsy: Bilateral posterior agyria-pachygyria. Dusunen Adam: The Journal of Psychiatry and Neurological Sciences 2015;28:175-8.

7. Valiente M, Marín O. Neuronal migration mechanisms in development and disease. Curr Opin Neurobiol 2010;20:68-78.

8. Dieterich K, Kimber E, Hall JG. Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care. Am J Med Genet C Semin Med Genet 2019;181:345-53.



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